JP6501896B2 - Substituted imidazo [1,2-a] pyridin-2-ylamine compounds and pharmaceutical compositions and methods of use thereof - Google Patents

Description

This application claims the benefit of priority of US Provisional Patent Application No. 62 / 109,028 filed Jan. 28, 2015, the disclosure of which is incorporated by reference The entire content is incorporated herein.

FIELD As used herein, substituted imidazo [1,2-a] pyridin-2-ylamine compounds and pharmaceutical compositions thereof; and their use for treating, preventing or ameliorating one or more symptoms of Janus kinase mediated disease Provide a way.

BACKGROUND The Janus kinase (JAK) signaling pathway is found in interferon-inducible receptor-mediated gene expression and has been shown to be a common signaling pathway used by many cytokines and growth factors. See, e.g., Darnell et al., Science 1994, 264, 1415-1421; Ihle, Nature 1995, 377, 591-594; Leonard et al., Annu. Rev. Immunol. 1998, 16, 293-322. The mammalian JAK family of intracellular tyrosine kinases has four members: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3) and tyrosine kinase 2 (TYK2). JAKs range in size from 120-140 kDa and contain seven conserved JAK homology (JH) domains, which define this kinase superfamily. See, for example, Gadina et al., Curr. Opin. Immunol. 2001, 13, 363-373.

  Binding of a cytokine to a cell surface receptor results in receptor dimerization followed by activation / phosphorylation of JAK tyrosine kinase which is structurally associated with the receptor. The particular tyrosine residue on the receptor is then phosphorylated by the activated JAK and used as a docking site for the latent cytoplasmic transcription factor family known as signal transduction and transcriptional activators (STATS). STATS is phosphorylated by JAK, dimerized and then translocated into the nucleus where it binds to specific DNA elements to activate gene transcription. See, eg, Villarino et al., J. Immunol. 2015, 194, 21-27.

  JAK is activated by a wide range of cytokines that play an essential role in immune function, inflammation and hematopoiesis. For example, see Hofmann et al., Curr. Opin. Allergy Clin. Immunol. 2002, 2, 495-506; O'Shea et al., Annu. Rev. Med. 2015, 66, 311-328. JAK1 and JAK3 can be activated by members of the common γ (γc) subfamily, ie, interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. However, these cytokines absolutely do not activate JAK2 or TYK2. The importance of these cytokines to the immune system is underscored by the observation of severe combined immunodeficiencies when loss of function mutations occur in these cytokines or JAK3. Another large cytokine subfamily sharing glycoprotein 130 (gp130) signaling subunits includes IL-6, IL-11, IL-27 and several other cytokines. Signaling of these cytokines always involves activation of JAK1 and also involves JAK2 and TYK2 consistently. IL-6 is involved in immune responses and excessive stimulation of this pathway is associated with various autoimmune and chronic inflammatory conditions. Numerous homodimeric receptors of erythropoietin (EPO), prolactin, thrombopoietin and growth hormone are known to activate JAK. The EPO pathway activates only JAK2 and is essential for red blood cell formation or erythropoiesis.

  Each JAK isoform can be used in multiple cytokine pathways, and thus inhibition of one or more JAKs can modulate the biological activity of many cytokines. See, for example, O'Shea et al., Annu. Rev. Med. 2015, 66, 311-328. Inhibition of JAK has various diseases and disorders, such as hyperproliferative disorders and cancer, such as leukemia and lymphoma, immune disorders and inflammatory disorders, such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergy, joints It may be useful to prevent, inhibit or treat the progression or development of rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis. For example, Quintas-Cardama et al., Nat. Rev. Drug Discov. 2011, 10, 127-140; O'Shea et al., Nat. Rev. Rheumatol. 2013, 9, 173-182; O'Shea et al. See, Annu. Rev. Med. 2015, 66, 311-328.

Darnell et al., Science 1994, 264, 1415-1421 Ihle, Nature 1995, 377, 591-594 Leonard et al., Annu. Rev. Immunol. 1998, 16, 293-322 Gadina et al., Curr. Opin. Immunol. 2001, 13, 363-373 Villarino et al., J. Immunol. 2015, 194, 21-27 Hofmann et al., Curr. Opin. Allergy Clin. Immunol. 2002, 2, 495-506 O'Shea et al., Annu. Rev. Med. 2015, 66, 311-328 Quintas-Cardama et al., Nat. Rev. Drug Discov. 2011, 10, 127-140 O'Shea et al., Nat. Rev. Rheumatol. 2013, 9, 173-182

SUMMARY OF THE DISCLOSURE Herein, Formula (A):

(In the formula:
L ¹ is hydrogen or -C (O) R ² ;
R ¹ in each occurrence is independently (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) ^{NR 1b R 1c, -OR 1a,} -OC (O) R 1a, -OC (O) OR 1a, -OC (O) NR 1b R 1c, -OC (= NR 1a) NR 1b R 1c, -OS ( O) R ^1a , -OS (O) ₂ R ^1a , -OS (O) NR ^1b R ^1c , -OS (O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , ^-NR 1a C (O) O ^{1d, -NR 1a C (O)} NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR 1a S (O) R 1d, -NR 1a S (O) 2 R 1d, - NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S (O) ₂ R ^1a , -S (O) NR ^1b R ^1c or -S (O) ₂ NR ^1b R ^1c ;
R ² is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ^A is C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ^L is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
Each R ^1a , R ^1b , R ^1c and R ^1d is independently hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ To C ₁₀ aryl, heteroaryl or heterocyclyl; or R ^1a and R ^1c together with the C and N atoms to which they are attached form a heterocyclyl; or R ^1b and R ^1c Together with the N atom to which they are attached form a heterocyclyl;
n is an integer of 0, 1, 2, 3 or 4;
Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q Wherein each Q is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl , C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q ^a ); and ^{(c) -C (O) R} a, -C (O) OR a, -C (O) NR b R c, -C (NR a) NR b R c, -OR a, -OC (O) R ^a ,- ^{OC (O) OR a, -OC} (O) NR b R c, -OC (= NR a) NR b R c, -OP (O) (OR a) 2, -OS (O) R a, -OS (O) ₂ R ^a , -OS (O) NR ^b R ^c , -S (O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C (O) R ^d , -NR ^a C (O ) OR ^d , -NR ^a C (O) NR ^b R ^c , -NR ^a C (= NR ^d ) NR ^b R ^c , -NR ^a S (O) R ^d , -NR ^a S (O) ₂ R ^{d , -NR a S (O) NR} b R c, -NR a S (O) 2 NR b R c, -SR a, -S (O) R a, -S (O) 2 R a, -S ( O) NR ^b R ^c and -S (O) ₂ NR ^b R ^{c are} independently selected from, wherein each R ^a , R ^b , R ^c and R ^d are independently (i) hydrogen; ii) C ₁ -C _{8 alkyl,} C 2 -C _{8 alkenyl,} C 2 -C _{8 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 6 _{-C 10} aryl, heteroaryl or heterocyclyl (each of which is 1 or more, an embodiment Are optionally substituted with 1, 2, 3 or 4 substituents Q ^a ) or (iii) R ^b and R ^c together with the N atom to which they are attached And forming a heterocyclyl optionally substituted with one or more, and in one embodiment 1, 2, 3 or 4 substituents Q ^a ;
Where each Q ^a is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl , C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl; and (c) -C (O) R ^f , -C (O) OR ^f , -C (O) NR ^g R ^h , -C (NR ^f ) NR ^{g R h, -OR f, -OC} (O) R f, -OC (O) OR f, -OC (O) NR g R h, -OC (= NR f) NR g R h, -OS (O ) R ^f , -OS (O) ₂ R ^f , -OS (O) NR ^g R ^h , -OS (O) ₂ NR ^g R ^h , -NR ^g R ^h , -NR ^f C (O) R ^k , ^{-NR f C (O) OR k} , -NR f C (O) NR g R h, -NR f C (= NR ^{) NR g R h, -NR f} S (O) R k, -NR f S (O) 2 R k, -NR f S (O) NR g R h, -NR f S (O) 2 NR g R ^{h, -SR f, -S (O} ) R f, -S (O) 2 R f, independently from the group consisting of -S (O) ^NR g ^{R h} and _{^{-S (O) 2 NR g R}} h Where each R ^f , R ^g , R ^h and R ^k are independently (i) hydrogen; (ii) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C _{8 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 6 _{-C 10} aryl, heteroaryl and heterocyclyl; or (iii) ^{R g} and ^{R h} are, together with the N atom to which they are attached a heterocyclyl Form a)
Or a single enantiomer, racemic mixture, diastereomeric mixture or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  Also, as used herein, Formula (I):

(Wherein, L ¹ , L ² , m, n, i, R ¹ , R ³ , R ⁴ and R ⁵ are as defined below)
Provided are imidazo [1,2-a] pyridin-2-ylamine compounds having the structure represented by: and pharmaceutically acceptable solvates, salts or prodrugs thereof.

  Additionally, provided herein are pharmaceutical compositions comprising any of the compounds provided herein and one or more pharmaceutically acceptable carriers.

  The compounds and compositions provided herein are useful for the treatment of diseases, disorders or conditions associated with JAK activity. Thus, as used herein, JAK-mediated diseases or disorders such as, but not limited to, rheumatoid arthritis, asthma, psoriasis, juvenile idiopathic arthritis, colitis, inflammatory bowel disease, lupus, alopecia, dry eye, IL6 The present invention provides a method for the treatment and / or prevention of diseases associated with hypersecretion of organelles, organ transplant rejection and proliferative diseases.

  The compounds provided herein may be used alone or in combination with other compounds disclosed herein or in combination with one or more other agents. Thus, herein, a therapeutically effective amount of a compound provided herein (eg, a compound of any one of Formulas (A)-(I)) and another compound provided herein (eg, a Formula The compound of any one of (A) to (I) and / or the combination with at least one other type of therapeutic agent is administered to a mammal in need of treatment, ie to a human patient Provided are methods for preventing, inhibiting or treating the diseases described herein.

  Provided herein is a method for modulating the activity of a tyrosine kinase, in one embodiment, a Janus kinase, comprising contacting the Janus kinase with a compound provided herein.

  Provided herein is a method for modulating the activity of a tyrosine kinase, in one embodiment Janus kinase, in a subject, comprising administering to the subject a compound provided herein. .

Provided herein are methods of synthesizing the compounds disclosed herein.
Embodiment 1: As used herein, Formula (I):

(In the formula:
L ¹ is selected from hydrogen and -C (O) R ² ;
L ² is a single ^{bond, -O -, - NR 6 -} , - C (O) -, - C (O) O -, - OC (O) -, - CONR 6 -, - NR 6 CO -, - _{S (O) 2 -, -} NR 6 SO 2 - and -S _(O) 2 NR ⁶ - is selected from;
m is an integer selected from 0 or 1 to 6;
n is 1, 2 or 3;
i is 1, 2, 3 or 4;
R ¹ in each occurrence is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, hydroxy, nitro, acyl, thio, thioalkoxy, thioaryloxy, thioheteroaryloxy, acylamino, alkoxy, amino, alkyl Amino, arylamino, heteroarylamino, amide, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and hetero Selected from arylalkyl;
R ² is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl;
R ³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, hetero Selected from arylthio, cyano, hydroxy, -OR ⁷ , -N (R ⁶ ) ₂ , -COR ⁷ and -CON (R ⁶ ) ₂ ;
R ⁴ in each occurrence independently is hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, acyl, acylamino, carboxy, cyano, amido, amino, alkylamino, arylamino, heteroarylamino, alkoxy, aryloxy, Selected from heteroaryloxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl (optionally substituted with 1 to 4 R ⁸ if possible); or 2 R ^{4 taken} together form a 3 to 9 membered ring, which ring optionally contains 1 to 4 heteroatoms independently selected from N, O and S And may be optionally substituted with 1 to 5 R ⁸ ;
R ⁵ is independently at each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, hydroxy, nitro, acyl, thio, thioalkoxy, thioaryloxy, thioheteroaryloxy, acylamino, alkoxy, amino, alkyl Amino, arylamino, heteroarylamino, amido, sulfinyl, sulfonyl, aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl Selected from;
R ⁶ in each occurrence is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or alternatively, two R ⁶ together form 3 to 9 Membered ring, which may optionally contain 1 to 4 heteroatoms independently selected from N, O and S, and may be 1 to 5 R ⁸ Optionally substituted at;
R ⁷ is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
R ⁸ independently at each occurrence of alkyl, alkenyl, alkynyl, haloalkyl, acyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, amino, cyano , nitro, ^{carboxy, -C (= O) OR 9} , - trifluoromethoxy, hydroxy, ^{thiol, -OR 9, -SR 9, -C} (= O) NR a R b, -NR a R b, -S (O) ₂ NR ^a R ^b , —S (O) ₂ R ⁹ , —NR ^a C (= O) R ⁹ and —OC (= O) R ⁹ ;
R ⁹ in each occurrence is independently hydrogen, C ₁ -C ₆ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R ^a and R ^b are each independently hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or alternatively, R ^a and R ^b together optionally, optionally Form a substituted 3 to 6 membered ring, which may optionally contain 1 or 2 heteroatoms independently selected from N, O and S)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Embodiment 2: In the compound of Embodiment 1, L ² is —CH ₂ — or —C (O) —.

Embodiment 3: In the compound of Embodiment 1 or 2, R ³ is optionally substituted cycloalkyl or heterocyclyl.

Embodiment 4 In the compound of Embodiment 3, R ³ is an optionally substituted 5- or 6-membered heterocyclyl.

Embodiment 5 In the compound of Embodiment 4, R ³ is:

It is selected from the group consisting of
Embodiment 6 In the compound of Embodiment 1, L ² is —O— and R ³ is lower alkyl.

Embodiment 7: In the compound of Embodiment 1, L ¹ is H.
Embodiment 8: In the compound of Embodiment 1, L ² is —CH ₂ — and R ³ is —CN.
Embodiment 9: In the compound according to any one of Embodiments 1 to 8, R ² is C _{1 to} C ₆ alkyl or C _{3 to} C ₆ cycloalkyl, wherein any of the above alkyl and cycloalkyl is each Optionally substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl and cyano ing.

Embodiment 10: In the compound of any one of Embodiments 1 to 9, R ¹ is hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl, amino, C ₁ -C ₆ alkylamino , Di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, nitro and cyano.

Embodiment 11: The compound of any one of Embodiments 1 to 10, wherein R ⁵ is hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl, amino, C ₁ -C ₆ alkylamino , Di- (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, nitro and cyano.

Embodiment 12: In the compound of any one of Embodiments 1 to 11, m = 0.
Embodiment 13 The compound of any one of the embodiments 1-11, wherein m = 1 and R ⁴ independently in each occurrence hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, acyl, acylamino, Selected from carboxy, cyano, amido, amino, alkylamino, arylamino, heteroarylamino, alkoxy, aryloxy, heteroaryloxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl, or 2 R ^{4 taken} together form a 3- to 6-membered ring, said ring optionally containing 1 to 3 heteroatoms independently selected from N, O and S And may be optionally substituted with 1 to 3 R ⁸ .

  Embodiment 14: As used herein:

Or a pharmaceutically acceptable salt, solvate or prodrug thereof, selected from the group consisting of

  Embodiment 15: A compound according to any one of the embodiments 1-14 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, as used herein. Provided is a composition comprising a diluent or a vehicle.

Embodiment 16 The composition of Embodiment 15 further comprises a second therapeutic agent.
Embodiment 17: The composition of Embodiment 16, wherein the second therapeutic agent is a different JAK inhibitor.

  Embodiment 18: A method of preventing or treating a disease or disorder associated with Janus kinase (JAK) activity herein, wherein a subject in need thereof has a therapeutically effective amount of Embodiments 1-2. 14. A method comprising administering a compound according to any one of 14 or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  Embodiment 19 The method of embodiment 18, wherein said disease or disorder is a disease or disorder mediated by Janus kinase (JAK) activity.

  Embodiment 20: The method of embodiment 19, wherein said JAK is selected from the group consisting of JAK1, JAK2, JAK3 and TYK2.

  Embodiment 21 The method of any one of embodiments 18 to 20, wherein the disease or disorder is rheumatoid arthritis, asthma, psoriasis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, lupus Alopecia, dry eye, diseases associated with hypersecretion of IL6, organ graft rejection and proliferative diseases.

  Embodiment 22: A method of inhibiting JAK activity in a subject herein, comprising contacting a biological sample of said subject with a compound according to any one of the embodiments 1-14, and inhibiting Providing a method comprising measuring an effect.

  Embodiment 23: A compound according to any one of Embodiments 1 to 14 or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for the treatment of a disease or disorder associated with JAK activity. Use of a solvate or prodrug or the composition of any one of embodiments 15-17 is provided.

FIG. 1 shows the effect of compound 14 on the arthritis score of rats in a collagen-induced arthritis model, where the symbol “**” indicates p <0.01. FIG. 2 shows the effect of Compound 14 on increasing rat foot volume in a collagen-induced arthritis model, where the symbol “*” indicates p <0.05. FIG. 3 shows the effect of compound 14 on the weight of rats in a collagen-induced arthritis rat model.

DETAILED DESCRIPTION In one embodiment, herein, Formula (A):

(In the formula:
L ¹ is hydrogen or -C (O) R ² ;
R ¹ in each occurrence is independently (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) ^{NR 1b R 1c, -OR 1a,} -OC (O) R 1a, -OC (O) OR 1a, -OC (O) NR 1b R 1c, -OC (= NR 1a) NR 1b R 1c, -OS ( O) R ^1a , -OS (O) ₂ R ^1a , -OS (O) NR ^1b R ^1c , -OS (O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , ^-NR 1a C (O) O ^{1d, -NR 1a C (O)} NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR 1a S (O) R 1d, -NR 1a S (O) 2 R 1d, - NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S (O) ₂ R ^1a , -S (O) NR ^1b R ^1c or -S (O) ₂ NR ^1b R ^1c ;
R ² is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ^A is C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ^L is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
Each R ^1a , R ^1b , R ^1c and R ^1d is independently hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ To C ₁₀ aryl, heteroaryl or heterocyclyl; or R ^1a and R ^1c together with the C and N atoms to which they are attached form a heterocyclyl; or R ^1b and R ^1c Together with the N atom to which they are attached form a heterocyclyl;
n is an integer of 0, 1, 2, 3 or 4;
Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q Wherein each Q is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl , C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q ^a ); and ^{(c) -C (O) R} a, -C (O) OR a, -C (O) NR b R c, -C (NR a) NR b R c, -OR a, -OC (O) R ^a ,- ^{OC (O) OR a, -OC} (O) NR b R c, -OC (= NR a) NR b R c, -OP (O) (OR a) 2, -OS (O) R a, -OS (O) ₂ R ^a , -OS (O) NR ^b R ^c , -S (O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C (O) R ^d , -NR ^a C (O ) OR ^d , -NR ^a C (O) NR ^b R ^c , -NR ^a C (= NR ^d ) NR ^b R ^c , -NR ^a S (O) R ^d , -NR ^a S (O) ₂ R ^{d , -NR a S (O) NR} b R c, -NR a S (O) 2 NR b R c, -SR a, -S (O) R a, -S (O) 2 R a, -S ( O) NR ^b R ^c and -S (O) ₂ NR ^b R ^{c are} independently selected from, wherein each R ^a , R ^b , R ^c and R ^d are independently (i) hydrogen; ii) C ₁ -C _{8 alkyl,} C 2 -C _{8 alkenyl,} C 2 -C _{8 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 6 _{-C 10} aryl, heteroaryl or heterocyclyl (each of which is 1 or more, an embodiment Are optionally substituted with 1, 2, 3 or 4 substituents Q ^a ) or (iii) R ^b and R ^c together with the N atom to which they are attached And forming a heterocyclyl optionally substituted with one or more, and in one embodiment 1, 2, 3 or 4 substituents Q ^a ;
Where each Q ^a is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl , C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl; and (c) -C (O) R ^f , -C (O) OR ^f , -C (O) NR ^g R ^h , -C (NR ^f ) NR ^{g R h, -OR f, -OC} (O) R f, -OC (O) OR f, -OC (O) NR g R h, -OC (= NR f) NR g R h, -OS (O ) R ^f , -OS (O) ₂ R ^f , -OS (O) NR ^g R ^h , -OS (O) ₂ NR ^g R ^h , -NR ^g R ^h , -NR ^f C (O) R ^k , ^{-NR f C (O) OR k} , -NR f C (O) NR g R h, -NR f C (= NR ^{) NR g R h, -NR f} S (O) R k, -NR f S (O) 2 R k, -NR f S (O) NR g R h, -NR f S (O) 2 NR g R ^{h, -SR f, -S (O} ) R f, -S (O) 2 R f, independently from the group consisting of -S (O) ^NR g ^{R h} and _{^{-S (O) 2 NR g R}} h Where each R ^f , R ^g , R ^h and R ^k are independently (i) hydrogen; (ii) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C _{8 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 6 _{-C 10} aryl, heteroaryl and heterocyclyl; or (iii) ^{R g} and ^{R h} are, together with the N atom to which they are attached a heterocyclyl Form a)
Or a single enantiomer, racemic mixture, diastereomeric mixture or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  In another embodiment, herein, Formula (I):

(In the formula:
L ¹ is selected from hydrogen and -C (O) R ² ;
L ² is a single ^{bond, -O -, - NR 6 -} , - C (O) -, - C (O) O -, - OC (O) -, - CONR 6 -, - NR 6 CO -, - _{S (O) 2 -, -} NR 6 SO 2 - and -S _(O) 2 NR ⁶ - is selected from;
m is an integer selected from 0 or 1 to 6;
n is an integer of 0, 1, 2 or 3;
i is an integer of 0, 1, 2, 3 or 4;
R ¹ is independently at each occurrence halogen, alkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, acyl, thio, thioalkoxy, thioaryloxy, thioheteroaryloxy, acylamino, alkoxy, amino, alkylamino, Selected from arylamino, heteroarylamino, amido, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, sulfonyl, carboxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
R ² is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl;
R ³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, hetero Selected from arylthio, cyano, hydroxy, -OR ⁷ , -N (R ⁶ ) ₂ , -COR ⁷ and -CON (R ⁶ ) ₂ ;
R ⁴ in each occurrence independently is hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, acyl, acylamino, carboxy, cyano, amido, amino, alkylamino, arylamino, heteroarylamino, alkoxy, aryloxy, Selected from heteroaryloxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl (optionally substituted with 1 to 4 R ⁸ if possible); or 2 R ^{4 taken} together form a 3 to 9 membered ring, said ring optionally comprising 1 to 4 heteroatoms independently selected from N, O and S And is optionally substituted with 1 to 5 R ⁸ ;
R ⁵ is independently at each occurrence halogen, alkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, acyl, thio, thioalkoxy, thioaryloxy, thioheteroaryloxy, acylamino, alkoxy, amino, alkylamino, Selected from arylamino, heteroarylamino, amido, sulfinyl, sulfonyl, aminosulfonyl, sulfonyl, carboxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
R ⁶ in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or alternatively, two R ⁶ together form 3 to 9 Membered ring, which optionally comprises 1 to 4 heteroatoms independently selected from N, O and S, and optionally 1 to 5 R ⁸ Selectively substituted;
R ⁷ is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
R ⁸ independently at each occurrence of alkyl, alkenyl, alkynyl, haloalkyl, acyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, amino, cyano , nitro, ^{carboxy, -C (= O) OR 9} , trifluoromethoxy, hydroxyl, ^{thiol, -OR 9, -SR 9, -C} (= O) NR a R b, -NR a R b, -S ( _{^{O) 2 NR a R b,}} -S (O) 2 R 9, is selected from ^{-NR a C (= O) R} 9 and -OC (= O) ^{R 9;}
R ⁹ in each occurrence is independently hydrogen, C ₁ -C ₆ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R ^a and R ^b are each independently hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; or alternatively, R ^a and R ^b together optionally, optionally Form a substituted 3 to 6 membered ring, said ring optionally comprising 1 or 2 heteroatoms independently selected from N, O and S)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  In yet another embodiment, herein, a therapeutically effective amount of a compound provided herein, alone or optionally, with a pharmaceutically acceptable carrier and / or one or more other agents. And a pharmaceutical composition comprising the combination of

  In yet another embodiment, a method of inhibiting the activity of the enzyme Janus kinase in a subject herein, alone or optionally, a compound provided herein to the subject. Provided in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent. In one embodiment, the subject is a mammal; in another embodiment, the subject is human; in another embodiment, the subject has a treatment with a disease or disorder associated with the activity of JAK. It is a human patient in need.

  Examples of diseases or disorders which are associated with the activity of the enzyme Janus kinase which can be prevented, inhibited or treated according to the present disclosure include, but are not limited to, diseases which are involved in cartilage destruction, bone and / or joint destruction, such as And / or conditions with inflammation or an immune response, such as Crohn's disease, rheumatoid arthritis, asthma rhinitis, psoriasis, juvenile idiopathic arthritis, ulcerative colitis, inflammatory bowel disease, lupus, IL6 Diseases or conditions associated with hypersecretion and transplant rejection, such as organ graft rejection. Also, inhibitors of JAK may be used in the treatment of proliferative diseases, in particular leukemia and solid tumors.

  In one embodiment, here, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. Arthritis, Crohn's disease, rheumatoid arthritis, psoriatic arthritis, asthma comprising administering in combination with one or more other compounds provided in and / or at least one other type of therapeutic agent , Psoriasis, juvenile idiopathic arthritis, colitis, inflammatory bowel disease, epilepsy, alopecia, dry eye, diseases or conditions associated with hypersecretion of IL6, progression or development of organ graft rejection or proliferative disease Provide a method for preventing, inhibiting or treating.

  In another embodiment, herein, a therapeutically effective amount of a compound provided herein, alone or optionally, to a mammalian patient, eg, a human patient, in need of prophylaxis, inhibition or treatment. Prevent, inhibit or treat the progression or development of osteoarthritis, including administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way to

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. To prevent, inhibit or treat the progression or development of Crohn's disease comprising administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way of

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. To prevent, inhibit or treat the progression or development of rheumatoid arthritis comprising administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way of

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. Prevents, inhibits or treats the progression or development of psoriatic arthritis comprising administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way to

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. For preventing, inhibiting or treating the progression or development of asthma, comprising administering in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way.

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. For preventing, inhibiting or treating the progression or development of psoriasis comprising administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way.

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. Prevent, inhibit or inhibit the progression or development of juvenile idiopathic arthritis comprising administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a method to treat.

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. Preventing, inhibiting or treating the progression or development of ulcerative colitis comprising administering in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way to

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. Preventing, inhibiting or treating the progression or development of inflammatory bowel disease, including administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way to

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. For preventing, inhibiting or treating the progression or development of epilepsy, including administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way.

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. Prevent, inhibit or treat the progression or development of organ graft rejection, including administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way to

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. To prevent, inhibit or treat the progression or development of alopecia, including administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way of

  In yet another embodiment, as used herein, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. To prevent, inhibit or treat the progression or development of dry eye, including administration in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way of

  In yet another embodiment, here, alone or optionally, a therapeutically effective amount of a compound provided herein to a mammalian patient, such as a human patient, in need of prophylaxis, inhibition or treatment. Preventing, inhibiting or treating the progression or development of a proliferative disease comprising administering in combination with one or more other compounds provided herein and / or at least one other type of therapeutic agent Provide a way to

Definitions In order to facilitate the understanding of the disclosure provided herein, certain terms are defined below.

  Generally, the nomenclature used herein and the laboratory procedures of biology, biochemistry, medicinal chemistry, organic chemistry and pharmacology described herein are well known in the art , Are commonly used. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

  The term "subject" refers to animals such as, but not limited to, primates (eg, humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats and mice. The terms "subject" and "patient" are used interchangeably herein, for example, with respect to a mammalian subject, such as a human subject, and in one embodiment a human.

The term "IC _50" or "EC _50" is in an assay measuring the response, the amount of compound required to the maximum 50% of inhibition of such responses, refers to a concentration or dosage.

The term "CC _50", the amount of compound that results in 50% reduction of host viability refers to the concentration or dosage. In certain embodiments, the CC ₅₀ of a compound is required to reduce the viability of cells treated with the compound by 50% relative to cells not treated with the compound Amount, concentration or dosage.

  The terms "about" or "approximately" mean an acceptable error for a particular value measured by one of ordinary skill in the art, which error is, in part, how the value is measured, Or depending on what is required. In certain embodiments, the terms "about" or "approximately" mean within 1, 2, 3 or 4 standard deviations. In certain embodiments, the terms "about" or "approximately" refer to 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6% of a given value or range. Means within 5%, 4%, 3%, 2%, 1%, 0.5% or 0.05%.

  The terms "active ingredient" and "active substance" refer to the treatment of one or more symptoms of a condition, disorder or disease in a subject, alone or in combination with one or more pharmaceutically acceptable excipients. , Compounds that are administered to prevent or ameliorate. As used herein, "active ingredient" and "active substance" may be optically active isomers or isotopic variants of the compounds described herein.

As used herein, the term "alkyl" refers to a branched saturated aliphatic hydrocarbon group containing 1 to 12 carbons, 1 to 8 carbons, or 1 to 4 carbons and a linear saturated aliphatic group It is intended to include both hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- Trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl and its various branched isomers are included, each of which may have 1 to 4 substituents, for example, halo (eg, F, Br, Cl or I ), CF ₃ , alkyl, alkoxy, aryl, aryloxy, aryl (aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, carboxamide, aminoacyl, aminocarboxy , Ruboxyamino, hydroxyl, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamide, alkanoylamino, arylcarbonylamino, nitro, cyano Optionally substituted with thiols, haloalkyls and / or trihaloalkyls. In certain embodiments, the alkyl group is one to four substituents, for example, halo (eg, F, Br, Cl or I), CF ₃ , alkyl, alkoxy, aryl, aryloxy, aryl ( Aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, carboxamide, aminoacyl, aminocarboxy, carboxyamino, hydroxyl, hydroxyalkyl, acyl, heteroaryl, heteroaryl Oxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamide, alkanoylamino, arylcar Niruamino, nitro, cyano, thiol, and is optionally substituted haloalkyl and / or trihaloalkyl. In certain embodiments, alkyl is optionally substituted with one or more substituents Q as described herein.

  Unless otherwise stated, the term "alkenyl" as used herein, alone or as part of another group, 2 to 12 carbons, including 1 to 6 carbon-carbon double bonds. , Straight or branched hydrocarbon radicals of 2 to 8 carbons or 2 to 6 carbons. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4 Heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl and 4,8,12-tetradecatrienyl, all of which may be from 1 to 4 substituents Ie, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl, heteroaryl, heterocyclyl, alkanoylamino, alkylamide, arylcarbonyl-amino, nitro, cyano, thiol, alkylthio And / or It is optionally substituted with any alkyl substituents shown in the specification. In certain embodiments, the alkenyl group is substituted by 1 to 4 substituents such as halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl, heteroaryl, Heterocyclyl, alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol, alkylthio and / or optionally substituted with any of the alkyl substituents indicated herein. In certain embodiments, alkenyl is optionally substituted with one or more substituents Q as described herein.

  Unless otherwise stated, the term "alkynyl" as used herein, alone or as part of another group, 2 to 12 carbons, 2 to 12 carbons, including one carbon-carbon triple bond. Refers to a straight or branched hydrocarbon radical of 8 carbons or 2 to 6 carbons. Examples of alkynyl groups include, but are not limited to, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl And 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl and 4-dodecynyl, all of which have 1 to 4 substituents, that is, halogen, haloalkyl, alkyl, alkoxy, alkenyl, Alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, heterocyclyl, hydroxyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol and / or alkylthio and / or any alkyl as indicated herein Replace In is optionally substituted. In certain embodiments, the alkynyl group is substituted by 1 to 4 substituents such as halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, heterocyclyl, Hydroxyl, alkanoylamino, alkylamide, arylcarbonylamino, nitro, cyano, thiol and / or alkylthio and / or optionally substituted with any of the alkyl substituents indicated herein. In certain embodiments, alkynyl is optionally substituted with one or more substituents Q as described herein.

  Unless otherwise stated, the term "cycloalkyl" as used herein, alone or as part of another group, is a saturated or partially unsaturated group comprising one to four rings or one or two rings. 3 to 15 cyclic hydrocarbon groups that are saturated (including one or two double bonds) but are non-aromatic, for example, containing a total of 3 to 20 ring carbon atoms It includes monocyclic alkyl, bicyclic alkyl (or bicycloalkyl), tricyclic alkyl and spirocyclic alkyl of ring member carbon or 3 to 10 ring member carbon. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, adamantinyl, (Z) -bicyclo [3.3.3] undes -2-enyl, bicyclo [3.3.3] -undecanyl, decahydronaphthalenyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and 7,7-dimethylbicyclo [2 .2.1] heptyl is exemplified, and each of these groups is one to four substituents, for example, halogen, alkyl, alkoxy, hydroxyl, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamide, Alkanoylamino, oxo, acyl, arylcarbo Arylamino, amino, nitro, cyano, thiol and / or alkylthio and / or "alkyl" is optionally substituted with any substituent as defined above. In certain embodiments, the cycloalkyl group is substituted by 1 to 4 substituents, such as halogen, alkyl, alkoxy, hydroxyl, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo Acyl, arylcarbonylamino, amino, nitro, cyano, thiol and / or alkylthio and / or optionally substituted with any of the substituents defined above for "alkyl". In certain embodiments, cycloalkyl is optionally substituted with one or more substituents Q as described herein.

  When an alkyl group as defined above has a single bond at two different carbon atoms for attachment to another group, this is referred to as an "alkylene" group and is optional as defined above for "alkyl". Selectively replaced.

  Where the alkenyl group as defined above and the alkynyl group as defined above each have a single bond for attachment at two different carbon atoms, these are referred to as an "alkenylene group" and an "alkynylene group", respectively It is optionally substituted as defined above for "alkenyl" and "alkynyl".

  The terms "halo" or "halogen" as used herein refer to fluoro, chloro, bromo, iodo.

  The term "haloalkyl" as used herein refers to an alkyl substituted with one or more halogens.

  Unless otherwise stated, the term "aryl" as used herein, alone or as part of another group, refers to a ring moiety (eg phenyl or naphthyl such as 1-naphthyl and 2-naphthyl) Monocyclic and bicyclic rings containing 6 to 10 carbons, optionally comprising 1 to 3 additional rings fused to a carbocyclic ring (eg aryl or cycloalkyl) It refers to the aromatic group of the formula. In certain embodiments, the aryl group is substituted with 1, 2 or 3 substituents via an available carbon atom, for example, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, tri Fluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, hetero Arylheteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, amino, substituted amino (wherein amino is one or two substituents (which may be alkyl, aryl, or And other optional aryl compounds mentioned above), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, Alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonylaminocarbonyl and / or any alkyl substitution as indicated herein Are optionally substituted with groups. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

  Unless otherwise stated, the terms "alkoxy", "aryloxy" or "aralkoxy" as used herein alone or as part of another group are any of the above linked to an oxygen atom Alkyl, aralkyl or aryl groups are included.

  Unless otherwise stated, the term "amino" as used herein, alone or as part of another group, represents one or two substituents (which may be the same or different). And, optionally, for example, optionally substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl Mean amino. Such substituent may be further substituted by any substituent defined by carboxyl and / or "alkyl". Also, the amino substituent, together with the nitrogen atom to which it is attached, is 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl, which may each be an alkyl, alkoxy, alkylthio, halo, It is optionally substituted with trifluoromethyl or hydroxyl.

  Unless otherwise stated, the terms "alkylthio", "arylthio" or "aralkylthio" as used herein, alone or as part of another group, are any of the above attached to a sulfur atom Alkyl, aralkyl or aryl groups are included.

  Unless otherwise stated, the terms "alkylamino", "arylamino" or "arylalkylamino" as used herein, alone or as part of another group, are attached to a nitrogen atom as described above And any alkyl, aryl or arylalkyl group of

  Unless otherwise stated, the terms "heterocyclyl", "heterocyclic system" or "heterocyclic ring" are saturated, partially unsaturated or unsaturated and include carbon atoms, N, NH, O and S. Or a stable non-aromatic 3-14 membered monocyclic, bicyclic, tricyclic, or three or four hetero atoms independently selected from the group consisting of It is intended to mean a spirocyclic ring. The nitrogen and sulfur heteroatoms may optionally be in oxidized form. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein are optionally substituted at the carbon or nitrogen atom with any of the substituents defined above for "alkyl" if the resulting compound is stable . Specifically stated, the nitrogen (N) in the heterocycle is optionally quaternized and the sulfur in the heterocycle is optionally substituted with one or two oxygens . If the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are preferably not adjacent to one another. In certain embodiments, heterocyclyl is optionally substituted with one or more substituents Q as described herein.

  Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H, 6H-1, 5, 2-dithiazinyl, 4-piperidonyl, 6H-1, 2, 5-thiadiazinyl, azocinyl, chromanyl, chromonyl, decahydroquinoli Nil, Dihydrofuran [2,3-b] Tetrahydrofuranyl, Imidazolidinyl, Imidazolinyl, Indolenyl, Indolinyl, Isochromanyl, Isoindolinyl, Morphonyl, Octahydroisoquinolinyl, Oxazolidinyl, Piperazinyl, Piperidinyl, Piperidinyl, 4-Piperidinyl, Pteridinyl, Pyranyl , Pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl and tetrahydroquinolinyl It is. In certain embodiments, heterocycles include, but are not limited to, piperidinyl, piperidinyl, 4-piperidinyl and piperonyl. The heterocyclyl rings described herein are optionally substituted with any of the substituents defined for "alkyl".

  As used herein, the term "aromatic heterocyclic system" or "heteroaryl" refers to a carbon atom and 1 to 4 hetero atoms independently selected from the group consisting of N, O and S. A stable 5- to 7-membered monocyclic or bicyclic or 7 to 10-membered bicyclic heterocyclic aromatic ring consisting of atoms (atam) and being essentially aromatic is meant Intended. The heteroaryl rings described herein are optionally substituted with any of the substituents defined for "alkyl". In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q as described herein.

  Examples of heteroaryl include, but are not limited to, 1H-indazolyl, indolyl, 4H-quinolizinyl, acridinyl, azocinyl, benzoimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, Benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazoronyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, decahydroquinolinyl, furanyl, furazanyl, imidazolyl, indazolyl, indolizinyl , Indolyl, isobenzofuranyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenalazinyl, Phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pterizinyl, purinyl, pyrazinyl, pyrazolyl, pyrazolotriazinyl, pyridazinyl, pyridoxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolyl, Quinazolinyl, quinolinyl, quinoxalinyl, carborinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3 1, 4-thiadiazolyl, tianthrenyl, thiazolyl, thienyl, thienothiazolyl, thieno oxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1 , 3,4-triazolyl, tetrazolyl and xanthenyl. In certain embodiments, examples of heteroaryl are indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothi Azolyl, benzimidazoronyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyrazolotriazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, Thiazolyl, thienyl and tetrazolyl. Examples of heteroaryl include, but are not limited to, pyridin-2 (1H) -one-yl, pyrimidine-2 (1H) -one-yl, pyrimidine-4 (3H) -one-yl and pyridazine-3 (2H) -On-yl is mentioned. In certain embodiments, examples of heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl , Benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzoisothiazinyl, dihydrobenzoisoxazinyl, dihydrofuryl, dihydroisoindolyl, Dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, Drinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidonyl, oxazolidinyl, oxiranyl , Piperazinyl, piperidinyl, 4-piperidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl and 1,3,5- Tritianil is mentioned. In certain embodiments, examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl And thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. In certain embodiments, examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazoli , Benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, And pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzoindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenalthazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and xanthenyl It can be mentioned.

  The term "cycloalkylalkyl" as used herein alone or as part of another group refers to a cycloalkyl group as defined above linked to an alkyl via a C atom.

  The terms "heterocyclylalkyl" or "heterocyclylalkenyl" as used herein, alone or as part of another group, are attached to an alkyl and alkenyl, respectively, through a C atom or a heteroatom, as described above Refers to the defined heterocyclyl group.

  The term "arylalkyl" as used herein alone or as part of another group refers to an aryl group as defined above linked to an alkyl via a C atom.

  The terms "heteroarylalkyl" or "heteroarylalkenyl" as used herein alone or as part of another group are each linked to an alkyl and alkenyl via a C atom or a heteroatom, respectively It refers to a heteroaryl group as defined above.

  Unless otherwise stated, the term "acyl" as used herein alone or as part of another group refers to an organic radical linked to a carbonyl (C = O) group; Examples of acyl groups include any group as defined above attached to a carbonyl and include, for example, alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl and cycloheteroalkanoyl.

The term "cyano" as used herein refers to the group -CN.
The term "nitro", as used herein, refers to a -NO ₂ group.

  The terms "hydroxy" or "hydroxyl" as used herein refer to an OH group.

  The term "pharmaceutically acceptable" as used herein is intended to mean that the compound, substance, composition and / or dosage form does not cause excessive toxicity, irritation, allergic reaction or other within the scope of sound medical judgment. Suitable for use in contact with human and animal tissues without problems or complications and meeting reasonable benefit / risk ratios. In one embodiment, each component is compatible with the other components of the pharmaceutical preparation and with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity or other problems or complications. "Pharmaceutically acceptable" in the sense that it is suitable for use in contact and meets a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy, 22nd ed .; The Pharmaceutical Press: 2012; Handbook of Pharmaceutical Excipients, 6th ed .; Rowe et al., Eds .; The Pharmaceutical Press: 2009; Handbook of Pharmaceutical Additives, 3rd ed .; See Ash and Ash Eds .; Synapse Information Resources, Inc .: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed .; Gibson Ed .; CRC Press: 2009.

  As used herein, “pharmaceutically acceptable salt” refers to a derivative of a compound of the present disclosure wherein the parent compound has been modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as mineral or organic acid salts of amines; acidic residues such as alkali or organic salts of carboxylic acids; . Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed by non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; and organic acids such as acetic acid, propione Acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy And salts prepared from benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.

  The pharmaceutically acceptable salts of the compounds disclosed herein may be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the compound in the form of the free acid or base with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or mixtures thereof. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is incorporated herein by reference in its entirety.

  Any compound that can be converted in vivo to provide a bioactive agent (ie, a compound disclosed herein) is a prodrug within the scope and spirit of the present disclosure.

  The term "prodrug" as used herein refers to the reaction of one or more of the hydroxyls of a compound disclosed herein with an alkyl, alkoxy or aryl substituted acylating agent using procedures known to those skilled in the art And esters and carbonates formed by forming acetate, pivalate, methyl carbon salt, benzoate and the like.

Various forms of prodrugs are well known in the art:
a) The Practice of Medicinal Chemistry, Wermuth et al., Ch. 31, (Academic Press, 1996);
b) Design of Prodrugs, edited by Bundgaard, (Elsevier, 1985);
c) A Textbook of Drug Design and Development, Krogsgaard-Larson and Bundgaard, eds. Ch. 5, pgs 113-191, (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Testa and Mayer, Wiley-VCH, 2003)
It is described in.

  Also, the compounds disclosed herein are isolated and purified after their preparation to obtain a composition containing the compound ("substantially pure") in an amount of 99% or more by weight. This is then used or formulated as described herein. Such "substantially pure" compounds are also contemplated herein.

  The compounds disclosed herein may have asymmetric centers. Compounds disclosed herein containing an asymmetric substitution atom can be isolated in optically active or racemic forms. Also, many geometric isomers of olefins, C = N double bonds, etc. may be present in the compounds disclosed herein, and all such stable isomers are contemplated herein. The cis and trans geometric isomers of the compounds disclosed herein may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic and all geometric isomeric forms of the compounds disclosed herein are contemplated herein unless a specific stereochemistry or isomeric form is specifically indicated. Be done.

  Where necessary, separation of the racemic mixture of the compounds disclosed herein may be by HPLC using a chiral column, or as described in Young et al., Antimicrob. Agents Chemother. 1995, 39, 2602-2605. It can be carried out by resolution using a resolving agent such as camphonic chloride.

  To the extent compounds or salts thereof disclosed herein may exist in tautomeric forms, all such tautomeric forms are contemplated herein.

  All stereoisomers of the compounds disclosed herein are contemplated herein either in admixture or in pure or substantially pure form. The compounds disclosed herein may have one or more asymmetric centers. As a result, the compounds disclosed herein may exist in enantiomeric or diastereomeric forms or mixtures thereof. In the process of preparation, racemates, enantiomers or diastereomers may be used as starting materials. If diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods, for example chromatography or fractional crystallization.

  "Stable compound" and "stable structure" ensure that the compound is sufficiently robust to survive isolation to a useful degree of purity from the reaction mixture and formulation into an effective therapeutic agent Intended to be shown.

  A “therapeutically effective amount” is effective to inhibit Janus kinase, or effective to treat, prevent or ameliorate one or more symptoms of Janus kinase mediated disease (eg, an inflammatory disorder) It is intended to encompass the amounts of the compounds disclosed herein in the amounts of the compounds disclosed herein alone or in combination with the compounds disclosed herein or in combination with other active ingredients. .

  As used herein, the terms "treat" or "treatment" encompass the treatment of a disease state in a mammal, particularly a human: (a) suppressing the development of the disease state in a mammal (Especially when such a mammal is predisposed to the disease state but has not yet been diagnosed as having the disease state); (b) inhibiting the disease state, ie arresting its onset And / or (c) alleviating the disease state, ie causing the elimination of the disease state.

The term "optionally substituted" refers to a group or substituent, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group, of one or more and in one or two embodiments. , 3 or 4 substituents Q, each of which is independently selected from, for example, (a) oxo (= O), cyano (-CN), halogen and nitro (- NO ₂ ); (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl, which are each 1 or more, an embodiment is optionally further substituted by 1, 2, 3 or 4 substituents ^{Q a} in the form); and ^{-C (O) R a, -C} (O) O ^{a, -C (O) NR b} R c, -C (NR a) NR b R c, -OR a, -OC (O) R a, -OC (O) OR a, -OC (O) NR b R ^c , -OC (= NR ^a ) NR ^b R ^c , -OS (O) R ^a , -OS (O) ₂ R ^a , -OS (O) NR ^b R ^c , -S (O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C (O) R ^d , -NR ^a C (O) OR ^d , -NR ^a C (O) NR ^b R ^c , -NR ^a C (= NR ^d ) NR ^b R ^c , -NR ^a S (O) R ^d , -NR ^a S (O) ₂ R ^d , -NR ^a S (O) NR ^b R ^c , -NR ^a S (O) ₂ NR ^b R ^{c _{, -SR a, -S (O)}} R a, -S (O) 2 R a, is selected from -S (O) ^NR b ^{R c} and ^{_{-S (O) 2 NR b R}} c, where each R ^a, R , ^{R c} and ^{R d} independently, (i) hydrogen; _(ii) C 1 ~C _{8 alkyl,} C 2 -C _{8 alkenyl,} C 2 -C _{8 alkynyl,} C 3 _{-C 10} cycloalkyl, _{C 6} -C ₁₀ aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q ^a ; or (Iii) R ^b and R ^c together with the N atom to which they are attached are optionally substituted one or more, and in one embodiment 1, 2, 3 or 4 substituents Q ^a It is intended to mean that it forms a substituted heterocyclyl. As used herein, unless otherwise stated, all groups that may be substituted are "optionally substituted".

In one embodiment, each Q ^a is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl; and (c) -C (O) R ^f , -C (O) OR ^f , -C (O) NR ^g R ^h , -C (NR ^{f ) NR g R h, -OR f} , -OC (O) R f, -OC (O) OR f, -OC (O) NR g R h, -OC (= NR f) NR g R h, -OS (O) R ^f , -OS (O) ₂ R ^f , -OS (O) NR ^g R ^h , -OS (O) ₂ NR ^g R ^h , -NR ^g R ^h , -NR ^f C (O) R ^k , -NR ^f C (O) OR ^k , -NR ^f C (O) NR ^g R ^h , -NR ^f C ( = NR ^k ) NR ^g R ^h , -NR ^f S (O) R ^k , -NR ^f S (O) ₂ R ^k , -NR ^f S (O) NR ^g R ^h , -NR ^f S (O) ₂ From the group consisting of NR ^g R ^h , -SR ^f , -S (O) R ^f , -S (O) ₂ R ^f , -S (O) NR ^g R ^h and -S (O) ₂ NR ^g R ^h Independently selected; wherein each R ^f , R ^g , R ^h and R ^k are independently (i) hydrogen; (ii) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl; or (iii) R ^g and R ^h together with the N atom to which they are attached And form a heterocyclyl.

The term "isotopic variant" refers to a compound that contains one or more isotopes of the atoms making up the compound in non-naturally occurring proportions. In certain embodiments, "isotopic variant" of a compound, one or more isotopes, such as, but not limited to, hydrogen ^{(1 H),} deuterium ^{(2 H),} tritium ^{(3 H),} carbon -11 ⁽¹¹ C), carbon ^{-12 (12} C), carbon ^{-13 (13} C), carbon ^{-14 (14} C), nitrogen ^{-13 (13} N), nitrogen ^{-14 (14} N), nitrogen -15 ⁽¹⁵ N), oxygen ^{-14 (14} O), oxygen ^{-15 (15} O), oxygen ^{-16 (16} O), oxygen ^{17 (17} O), oxygen ^{-18 (18} O), fluorine 17 ⁽¹⁷ F), fluorine ^{-18 (18} F), phosphorus ^{-31 (31} P), phosphorus ^{-32 (32} P), phosphorus ^{-33 (33} P), sulfur ^{-32 (32} S), sulfur ^{-33 (33} S) , Sulfur-34 ( ³⁴ S), sulfur-35 ( ³⁵ S), sulfur-36 ( ^{3 6} S), chlorine ^-35 (35 Cl), chlorine ^-36 (36 Cl), chlorine ^-37 (37 Cl), bromine ^-79 (79 Br), bromine ^-81 (81 Br), iodine -123 ⁽¹²³ I ), iodine -125 ⁽¹²⁵ I), iodine -127 ⁽¹²⁷ I), those containing at a ratio not iodine -129 ⁽¹²⁹ I) and iodine -131 to ⁽¹³¹ I) exist in nature. In certain embodiments, "isotopic variants" of the compounds are in a stable form, ie non-radioactive. In certain embodiments, "isotopic variant" of a compound, one or more isotopes, such as, but not limited to, hydrogen ⁽¹ H), deuterium ⁽² H), carbon ^{-12 (12} C) carbon ^{-13 (13} C), nitrogen ^{-14 (14} N), nitrogen ^{-15 (15} N), oxygen ^{-16 (16} O), oxygen ^{-17 (17} O), oxygen ^{-18 (18} O), fluorine -17 ( ¹⁷ F), phosphorus-31 ( ³¹ P), sulfur-32 ( ³² S), sulfur-33 ( ³³ S), sulfur-34 ( ³⁴ S), sulfur-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl), chlorine-37 ( ³⁷ Cl), bromine- ⁷⁹ ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br) and iodine- ¹²⁷ ( ¹²⁷ I) in non-naturally occurring proportions . In certain embodiments, "isotopic variants" of a compound are unstable forms, ie, radioactive. In certain embodiments, "isotopic variant" of a compound, one or more isotopes, such as but not limited to tritium ⁽³ H), carbon ^{-11 (11} C), carbon -14 ⁽¹⁴ C ), nitrogen ^{-13 (13} N), oxygen ^{-14 (14} O), oxygen ^{-15 (15} O), fluorine ^{-18 (18} F), phosphorus ^{-32 (32} P), phosphorus ^{-33 (33} P), Sulfur-35 ( ³⁵ S), chlorine-36 ( ³⁶ Cl), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-129 ( ¹²⁹ I) and iodine-131 ( ¹³¹ I) naturally It contains in the ratio which does not exist. In the compounds provided herein, any hydrogen can be, for example, ² H, or any carbon can be, by way of example, ¹³ C, as is feasible at the discretion of one of ordinary skill in the art, or any It will be appreciated that the nitrogen may be ¹⁵ N by way of example and that any oxygen may be ¹⁸ O. In certain embodiments, "isotopic variants" of a compound are those that contain deuterium in non-naturally occurring proportions.

  The term "solvate" refers to one or more molecules of a solute, such as a compound disclosed herein and one or more molecules of a solvent, which are presented in stoichiometric or non-stoichiometric amounts And complexes or aggregates formed by Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in non-crystalline form. If the solvent is water, the solvate is a hydrate. Examples of hydrates include but are not limited to hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and pentahydrate.

  As used herein, abbreviations for any protecting groups, amino acids and other compounds, unless otherwise indicated, conform to conventional methods or are recognized abbreviations, eg, J. Org. Chem. 2007. , 72, 23A-24A or as established by the IUPAC-IUB Commission on Biochemical Nomenclature (Biochem. 1972, 11, 942-944).

Compounds In one embodiment, herein, Formula (A):

(In the formula:
L ¹ is hydrogen or -C (O) R ² ;
R ¹ in each occurrence is independently (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) ^{NR 1b R 1c, -OR 1a,} -OC (O) R 1a, -OC (O) OR 1a, -OC (O) NR 1b R 1c, -OC (= NR 1a) NR 1b R 1c, -OS ( O) R ^1a , -OS (O) ₂ R ^1a , -OS (O) NR ^1b R ^1c , -OS (O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , ^-NR 1a C (O) O ^{1d, -NR 1a C (O)} NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR 1a S (O) R 1d, -NR 1a S (O) 2 R 1d, - NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S (O) ₂ R ^1a , -S (O) NR ^1b R ^1c or -S (O) ₂ NR ^1b R ^1c ;
R ² is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ^A is C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ^L is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
Each R ^1a , R ^1b , R ^1c and R ^1d is independently hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ To C ₁₀ aryl, heteroaryl or heterocyclyl; or R ^1a and R ^1c together with the C and N atoms to which they are attached form a heterocyclyl; or R ^1b and R ^1c Together with the N atom to which they are attached form a heterocyclyl;
n is an integer of 0, 1, 2, 3 or 4;
Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q Wherein each Q is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q ^a ; and ^{(c) -C (O) R} a, -C (O) OR a, -C (O) NR b R c, -C (NR a) NR b R c, -OR a, -OC (O ) ^Ra , ^{-OC (O) OR a, -OC} (O) NR b R c, -OC (= NR a) NR b R c, -OP (O) (OR a) 2, -OS (O) R a, - _{^{OS (O) 2 R a,}} -OS (O) NR b R c, -S (O) 2 NR b R c, -NR b R c, -NR a C (O) R d, -NR a C ( O) OR ^d , -NR ^a C (O) NR ^b R ^c , -NR ^a C (= NR ^d ) NR ^b R ^c , -NR ^a S (O) R ^d , -NR ^a S (O) ₂ R ^{d, -NR a S (O)} NR b R c, -NR a S (O) 2 NR b R c, -SR a, -S (O) R a, -S (O) 2 R a, -S (O) NR ^b R ^c and —S (O) ₂ NR ^b R ^c independently selected from, wherein each R ^a , R ^b , R ^c and R ^d independently is (i) hydrogen; (ii) C -C _{8 alkyl,} C 2 -C _{8 alkenyl,} C 2 -C _{8 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 6 _{-C 10} aryl, heteroaryl or heterocyclyl (each of which is 1 or more, an embodiment Are optionally substituted with 1, 2, 3 or 4 substituents Q ^a ) or (iii) R ^b and R ^c together with the N atom to which they are attached And forming a heterocyclyl optionally substituted with one or more, and in one embodiment 1, 2, 3 or 4 substituents Q ^a ;
Where each Q ^a is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl , C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl; and (c) -C (O) R ^f , -C (O) OR ^f , -C (O) NR ^g R ^h , -C (NR ^f ) NR ^{g R h, -OR f, -OC} (O) R f, -OC (O) OR f, -OC (O) NR g R h, -OC (= NR f) NR g R h, -OS (O ) R ^f , -OS (O) ₂ R ^f , -OS (O) NR ^g R ^h , -OS (O) ₂ NR ^g R ^h , -NR ^g R ^h , -NR ^f C (O) R ^k , ^{-NR f C (O) OR k} , -NR f C (O) NR g R h, -NR f C (= NR ^{) NR g R h, -NR f} S (O) R k, -NR f S (O) 2 R k, -NR f S (O) NR g R h, -NR f S (O) 2 NR g R ^{h, -SR f, -S (O} ) R f, -S (O) 2 R f, independently from the group consisting of -S (O) ^NR g ^{R h} and _{^{-S (O) 2 NR g R}} h Where each R ^f , R ^g , R ^h and R ^k are independently (i) hydrogen; (ii) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C _{8 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 6 _{-C 10} aryl, heteroaryl and heterocyclyl; or (iii) ^{R g} and ^{R h} are, together with the N atom to which they are attached a heterocyclyl Form a)
Or a single enantiomer, racemic mixture, diastereomeric mixture or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In one embodiment, in Formula (A):
L ¹ is hydrogen or -C (O) R ² ;
R ¹ in each occurrence independently is (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q); or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) NR ^1b R ^1c , -OR ^1a , -OC (O) R ^1a , -OC (O) OR ^1a , -OC ( ^{O) NR 1b R 1c, -OC} (= NR 1a) NR 1b R 1c, -OS (O) R 1a, -OS (O) 2 R 1a, -OS (O) NR 1b R 1c, -OS (O ) ₂ NR ^1b R ^1c, -NR ^{b R 1c, -NR 1a C (} O) R 1d, -NR 1a C (O) OR 1d, -NR 1a C (O) NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR ^1a S (O) R ^1d , -NR ^1a S (O) ₂ R ^1d , -NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , _{^{-S (O) R 1a, -S}} (O) be ^{2 R 1a, -S (O)} NR 1b R 1c or _{^{-S (O) 2 NR 1b R}} 1c;
R ² is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl (each of which is 1 Optionally substituted by one or more substituents Q);
R ^A is C ₆ -C ₁₀ aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q;
R ^L is hydrogen;
n is an integer of 0, 1, 2, 3 or 4;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in Formula (A):
L ¹ is hydrogen or -C (O) R ² ;
R ¹ in each occurrence independently is (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q); or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) NR ^1b R ^1c , -OR ^1a , -OC (O) R ^1a , -OC (O) OR ^1a , -OC ( ^{O) NR 1b R 1c, -OC} (= NR 1a) NR 1b R 1c, -OS (O) R 1a, -OS (O) 2 R 1a, -OS (O) NR 1b R 1c, -OS (O ) ₂ NR ^1b R ^1c, -NR ^{b R 1c, -NR 1a C (} O) R 1d, -NR 1a C (O) OR 1d, -NR 1a C (O) NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR ^1a S (O) R ^1d , -NR ^1a S (O) ₂ R ^1d , -NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , _{^{-S (O) R 1a, -S}} (O) be ^{2 R 1a, -S (O)} NR 1b R 1c or _{^{-S (O) 2 NR 1b R}} 1c;
R ² is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl (each of which is 1 Optionally substituted by one or more substituents Q);
R ^A is C ₆ -C ₁₀ aryl, which is optionally substituted with one or more substituents Q);
R ^L is hydrogen;
n is an integer of 0, 1, 2, 3 or 4;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is hydrogen or -C (O) R ² ;
R ¹ in each occurrence independently is (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q); or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) NR ^1b R ^1c , -OR ^1a , -OC (O) R ^1a , -OC (O) OR ^1a , -OC ( ^{O) NR 1b R 1c, -OC} (= NR 1a) NR 1b R 1c, -OS (O) R 1a, -OS (O) 2 R 1a, -OS (O) NR 1b R 1c, -OS (O ) ₂ NR ^1b R ^1c, -NR ^{b R 1c, -NR 1a C (} O) R 1d, -NR 1a C (O) OR 1d, -NR 1a C (O) NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR ^1a S (O) R ^1d , -NR ^1a S (O) ₂ R ^1d , -NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , _{^{-S (O) R 1a, -S}} (O) be ^{2 R 1a, -S (O)} NR 1b R 1c or _{^{-S (O) 2 NR 1b R}} 1c;
R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl, each of which is optionally substituted with one or more substituents Q;
R ^A is C ₆ -C ₁₀ aryl, which is optionally substituted with one or more substituents Q);
R ^L is hydrogen;
n is an integer of 0, 1, 2, 3 or 4;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is —C (O) R ² where R ² is C ₃ -C ₁₀ cycloalkyl which is optionally substituted with one or more substituents Q;
R ¹ in each occurrence independently is (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q); or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) NR ^1b R ^1c , -OR ^1a , -OC (O) R ^1a , -OC (O) OR ^1a , -OC ( ^{O) NR 1b R 1c, -OC} (= NR 1a) NR 1b R 1c, -OS (O) R 1a, -OS (O) 2 R 1a, -OS (O) NR 1b R 1c, -OS (O ) ₂ NR ^1b R ^1c, -NR ^{b R 1c, -NR 1a C (} O) R 1d, -NR 1a C (O) OR 1d, -NR 1a C (O) NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR ^1a S (O) R ^1d , -NR ^1a S (O) ₂ R ^1d , -NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , _{^{-S (O) R 1a, -S}} (O) be ^{2 R 1a, -S (O)} NR 1b R 1c or _{^{-S (O) 2 NR 1b R}} 1c;
R ^A is C ₆ -C ₁₀ aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q;
R ^L is hydrogen;
n is an integer of 0, 1, 2, 3 or 4;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is —C (O) R ² , wherein R ² is cyclopropyl or cyclobutyl;
R ¹ in each occurrence independently is (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q); or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) NR ^1b R ^1c , -OR ^1a , -OC (O) R ^1a , -OC (O) OR ^1a , -OC ( ^{O) NR 1b R 1c, -OC} (= NR 1a) NR 1b R 1c, -OS (O) R 1a, -OS (O) 2 R 1a, -OS (O) NR 1b R 1c, -OS (O ) ₂ NR ^1b R ^1c, -NR ^{b R 1c, -NR 1a C (} O) R 1d, -NR 1a C (O) OR 1d, -NR 1a C (O) NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR ^1a S (O) R ^1d , -NR ^1a S (O) ₂ R ^1d , -NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , _{^{-S (O) R 1a, -S}} (O) be ^{2 R 1a, -S (O)} NR 1b R 1c or _{^{-S (O) 2 NR 1b R}} 1c;
R ^A is C ₆ -C ₁₀ aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q;
R ^L is hydrogen;
n is an integer of 0, 1, 2, 3 or 4;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl (these Each is optionally substituted with one or more substituents Q);
R ¹ in each occurrence is independently halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^A is C ₆ -C ₁₀ aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q;
R ^L is hydrogen;
n is an integer of 0, 1 or 2;
Each Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl or heterocyclyl (each of which is one or more substituents And are optionally substituted);
R ¹ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^A is C ₆ -C ₁₀ aryl, which is substituted with one or more substituents Q;
R ^L is hydrogen;
n is an integer of 0 or 1;
Each Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl (each of which is optionally substituted with one or more substituents Q) Selectively substituted);
R ¹ is halogen or C ₁ -C ₈ alkyl (which is optionally substituted with one or more substituents Q);
R ^A is phenyl substituted with one or two substituents Q, wherein each Q is independently halogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl,- C (O) R ^a , -OR ^a or -NR ^a S (O) R ^d ; said alkyl and cycloalkyl are optionally further substituted with one or two substituents Q ^a ;
R ^L is hydrogen;
n is an integer of 0 or 1;
Each R ^a , R ^d , Q and Q ^a is as defined herein.

In another embodiment, in formula (A):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl (each of which is optionally substituted with one or more substituents Q) Selectively substituted);
R ¹ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^A is phenyl substituted with one or two substituents Q, wherein each Q is independently halogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl,- C ^(O) R a, be -OR ^a or ^{-NR a S (O) R d} ; wherein, ^{R a} is hydrogen, methyl or dimethyl azetidinyloxyimino; ^{R d} is cyclopropyl; said alkyl And cycloalkyl are optionally further substituted with one or two substituents Q ^a ; wherein each Q ^a is independently cyano, 3,3,3-trifluoropropanamide, Dimethylazetidinyl, hydroxypyrrolidinyl, piperidinyl, cyanopiperidinyl, morpholino, methylpiperazinyl, 1,1-dioxide thiomorpholino or cyanomethylphenylamino
R ^L is hydrogen;
n is an integer of 0 or 1;
Each Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl (each of which is optionally substituted with one or more substituents Q) Selectively substituted);
R ¹ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^A is phenyl substituted with one or two substituents Q, wherein each Q is independently fluoro, methyl, cyanomethyl, cyanoethyl, (3,3,3-trifluoropropane Amido) methyl, dimethylazetidinylmethyl, (hydroxypyrrolidinyl) methyl, piperidinylmethyl, cyanopiperidinyl-methyl, morpholinomethyl, (methylpiperazinyl) methyl, (1,1-dioxide thiomorpholino ) Methyl, (cyanomethylphenylamino) methyl, cyanocyclopropyl, methoxy, dimethylazetidinecarbonyl or cyclopropanesulfonamide;
R ^L is hydrogen;
n is an integer of 0 or 1;
Each Q is as defined herein.

In another embodiment, in formula (A):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl;
R ¹ is halogen or C ₁ -C ₈ alkyl;
R ^A is phenyl substituted with one or two substituents Q, wherein each Q is independently fluoro, methyl, cyanomethyl, cyanoethyl, (3,3,3-trifluoropropane Amido) methyl, dimethylazetidinylmethyl, (hydroxypyrrolidinyl) methyl, piperidinylmethyl, cyanopiperidinyl-methyl, morpholinomethyl, (methylpiperazinyl) methyl, (1,1-dioxide thiomorpholino ) Methyl, (cyanomethylphenylamino) methyl, cyanocyclopropyl, methoxy, dimethylazetidinecarbonyl or cyclopropanesulfonamide;
R ^L is hydrogen;
n is an integer of 0 or 1.

In another embodiment, in formula (A):
L ¹ is hydrogen or —C (O) R ² , wherein R ² is isopropyl, cyclopropyl or cyclobutyl;
R ¹ is fluoro, chloro or methyl;
R ^A is cyanomethyl-phenyl, cyanomethyl-fluorophenyl, (cyanoethyl) phenyl, (cyanocyclopropyl) phenyl, ((3,3,3-trifluoropropanamido) methyl) phenyl, (dimethylazetidinyl-methyl) phenyl , ((Hydroxypyrrolidinyl) methyl) phenyl, (piperidinylmethyl) phenyl, ((cyano-piperidinyl) methyl) phenyl, (morpholinomethyl) phenyl, ((methyl piperazinyl) methyl) phenyl, ((1 , 1-dioxidethiomorpholino) methyl) phenyl, fluoro-((1,1-dioxidethiomorpholino) methyl) -phenyl, methyl-((1,1-dioxidethiomorpholino) methyl) phenyl, methoxyphenyl, ((Cyanomethyl-phenylamino) methyl ) Phenyl, (dimethylazetidinecarbonyl) -phenyl, fluoro- (dimethylazetidine-carbonyl) phenyl or (cyclopropanesulfonamide) phenyl;
R ^L is hydrogen;
n is an integer of 0 or 1.

In another embodiment, in formula (A):
L ¹ is hydrogen or —C (O) R ² , wherein R ² is isopropyl, cyclopropyl or cyclobutyl;
R ¹ is fluoro, chloro or methyl;
R ^A is 4-cyanomethylphenyl, 2-fluoro-4-cyanomethylphenyl, 3-fluoro-4-cyano-methylphenyl, 4- (1-cyanoethyl) phenyl, 4- (1-cyanocyclopropyl) phenyl, 4-((3,3,3-Trifluoro-propanamido) -methyl) phenyl, 4- (3,3-dimethylazetidin-1-ylmethyl) phenyl, 4-((3-hydroxy-pyrrolidine-1-) Yl) methyl) phenyl, (R) -4-((3-hydroxypyrrolidin-1-yl) methyl) phenyl, (S) -4-((3-hydroxypyrrolidin-1-yl) methyl) phenyl, 4- (Piperidin-1-ylmethyl) phenyl, 4-((4-cyanopiperidin-1-yl) methyl) phenyl, 4- (morpholinomethyl) phenyl, 4- (4- (morpholinomethyl) phenyl) (4-Methyl-piperazin-1-yl) methyl) -phenyl, 3-((1,1-dioxidethiomorpholino) methyl) phenyl, 4-((1,1-dioxidethiomorpholino) -methyl) phenyl , 2-fluoro-4-((1,1-dioxide thiomorpholino) -methyl) phenyl, 3-fluoro-4-((1,1-dioxide thiomorpholino) -methyl) phenyl, 2-methyl-4 -((1,1-dioxidethiomorpholino) methyl) -phenyl, 4-methoxyphenyl, 4-((2-cyanomethylphenylamino) -methyl) phenyl, 4- (3,3-dimethyl-azetidine-1 -Carbonyl) phenyl, 2-fluoro-4- (3,3-dimethyl-azetidine-1-carbonyl) phenyl, 3-fluoro-4- (3,3-dimethylazetic) Down-1-carbonyl) phenyl or 4- (cyclopropanesulfonamide) phenyl;
R ^L is hydrogen;
n is an integer of 0 or 1.

In yet another embodiment, in Formula (A):
L ¹ is —C (O) R ² wherein R ² is isopropyl, cyclopropyl or cyclobutyl;
R ¹ is fluoro, chloro or methyl;
R ^A is 4-cyanomethylphenyl, 2-fluoro-4-cyanomethylphenyl, 3-fluoro-4-cyano-methylphenyl, 4- (1-cyanoethyl) phenyl, 4- (1-cyanocyclopropyl) phenyl, 4-((3,3,3-Trifluoro-propanamido) -methyl) phenyl, 4- (3,3-dimethylazetidin-1-ylmethyl) phenyl, 4-((3-hydroxy-pyrrolidine-1-) Yl) methyl) phenyl, (R) -4-((3-hydroxypyrrolidin-1-yl) methyl) phenyl, (S) -4-((3-hydroxypyrrolidin-1-yl) methyl) phenyl, 4- (Piperidin-1-ylmethyl) -phenyl, 4-((4-cyano-piperidin-1-yl) methyl) phenyl, 4- (morpholinomethyl) phenyl, 4 -((4-Methyl-piperazin-1-yl) -methyl) phenyl, 3-((1,1-dioxidethiomorpholino) methyl) phenyl, 4-((1,1-dioxide-thiomorpholino) methyl) Phenyl, 2-fluoro-4-((1,1-dioxide thiomorpholino) methyl) phenyl, 3-fluoro-4-((1,1-dioxide thiomorpholino) -methyl) phenyl, 2-methyl-4 -((1,1-dioxide-thiomorpholino) methyl) phenyl, 4-methoxyphenyl, 4-((2-cyanomethylphenylamino) -methyl) -phenyl, 4- (3,3-dimethylazetidine-1 -Carbonyl) phenyl, 2-fluoro-4- (3,3-dimethyl-azetidine-1-carbonyl) phenyl, 3-fluoro-4- (3,3-dimethylaze L- carbonyl) phenyl or 4- (cyclopropane - sulfonamido) phenyl;
R ^L is hydrogen;
n is an integer of 0 or 1.

  In another embodiment, herein, Formula (B):

(Wherein, R ¹ , R ^A and n are each as defined herein)
Or a single enantiomer, racemic mixture, diastereomeric mixture or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  In another embodiment, herein, Formula (C):

(In the formula:
L ¹ is hydrogen or -C (O) R ² ;
L ² is a single ^{bond, -O -, - NR 6 -} , - C (O) -, - C (O) O -, - OC (O) -, - CONR 6 -, - NR 6 CO -, - _{S (O) 2 -, -} NR 6 SO 2 - or _-SO 2 NR ⁶ - a and;
m is an integer of 0, 1, 2, 3, 4, 5 or 6;
n is an integer of 0, 1, 2 or 3;
i is an integer of 0, 1, 2, 3 or 4;
R ^L is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ¹ in each occurrence is independently (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) ^{NR 1b R 1c, -OR 1a,} -OC (O) R 1a, -OC (O) OR 1a, -OC (O) NR 1b R 1c, -OC (= NR 1a) NR 1b R 1c, -OS ( O) R ^1a , -OS (O) ₂ R ^1a , -OS (O) NR ^1b R ^1c , -OS (O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , ^-NR 1a C (O) O ^{1d, -NR 1a C (O)} NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR 1a S (O) R 1d, -NR 1a S (O) 2 R 1d, - NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S (O) ₂ R ^1a , -S (O) NR ^1b R ^1c or -S (O) ₂ NR ^1b R ^1c ;
R ² is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl;
R ³ is (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl; or ^{(c) -C (O) R} 1a, -C (O) oR 1a, -C (O) NR 1b R 1c, -C (NR 1a) NR 1b R 1c, -OR ^{1a, -OC (O) R 1a} , -OC (O) OR 1a, -OC (O) NR 1b R 1c, -OC (= NR 1a) NR 1b R 1c, -OS (O) R 1a, -OS (O) ₂ R ^1a , -OS (O) NR ^1b R ^1c , -OS (O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , -NR ^1a C (O ) OR ^1d , -NR ^1a C ( ^{O) NR 1b R 1c, -NR} 1a C (= NR 1d) NR 1b R 1c, -NR 1a S (O) R 1d, -NR 1a S (O) 2 R 1d, -NR 1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S (O) ₂ R ^1a , -S (O) NR ^1b R ^1c or -S (O) ₂ NR ^1b R ^1c ;
R ⁴ in each occurrence is independently (a) hydrogen, cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^{1a) NR 1b R 1c, -OR} 1a, -OC (O) R 1a, -OC (O) OR 1a, -OC (O) NR 1b R 1c, -OC (= NR 1a) NR 1b R 1c, - _{^{OS (O) R 1a, -OS}} (O) 2 R 1a, -OS (O) NR 1b R 1c, -OS (O) 2 NR 1b R 1c, -NR 1b R 1c, -NR 1a C (O) R ^{1d, -NR} 1a C ( ^{) OR 1d, -NR 1a C (} O) NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR 1a S (O) R 1d, -NR 1a S (O) 2 R 1d , -NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S (O) ₂ R ^1a , -S ( O) NR ^{1 b} R ^{1 c} or —S (O) ₂ NR ^{1 b} R ^{1 c} ; or two R ⁴ groups together with the C atom to which they are attached, a C ₃ -C ₁₀ cyclo Form an alkyl or heterocyclyl;
R ⁵ is independently in each occurrence (a) cyano, halogen or nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a , -C (O) OR ^1a , -C (O) NR ^1b R ^1c , -C (NR ^1a ) ^{NR 1b R 1c, -OR 1a,} -OC (O) R 1a, -OC (O) OR 1a, -OC (O) NR 1b R 1c, -OC (= NR 1a) NR 1b R 1c, -OS ( O) R ^1a , -OS (O) ₂ R ^1a , -OS (O) NR ^1b R ^1c , -OS (O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , ^-NR 1a C (O) O ^{1d, -NR 1a C (O)} NR 1b R 1c, -NR 1a C (= NR 1d) NR 1b R 1c, -NR 1a S (O) R 1d, -NR 1a S (O) 2 R 1d, - NR ^1a S (O) NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S (O) ₂ R ^1a , -S (O) NR ^1b R ^1c or -S (O) ₂ NR ^1b R ^1c ;
R ⁶ in each occurrence is independently hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, hetero. Aryl or heterocyclyl;
Each R ^1a , R ^1b , R ^1c and R ^1d is independently hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ To C ₁₀ aryl, heteroaryl or heterocyclyl; or R ^1a and R ^1c together with the C and N atoms to which they are attached form a heterocyclyl; or R ^1b and R ^1c Together with the N atom to which they are attached form a heterocyclyl;
Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q Wherein each Q is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cyclo. Alkyl, C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl, each of which is optionally further substituted with one or more, in one embodiment 1, 2, 3 or 4 substituents Q ^a ; and ^{(c) -C (O) R} a, -C (O) OR a, -C (O) NR b R c, -C (NR a) NR b R c, -OR a, -OC (O ) ^Ra , ^{-OC (O) OR a, -OC} (O) NR b R c, -OC (= NR a) NR b R c, -OS (O) R a, -OS (O) 2 R a, -OS ( O) NR ^b R ^c , -S (O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C (O) R ^d , -NR ^a C (O) OR ^d , -NR ^a C (O ) NR ^b R ^c , -NR ^a C (= NR ^d ) NR ^b R ^c , -NR ^a S (O) R ^d , -NR ^a S (O) ₂ R ^d , -NR ^a S (O) NR ^b R ^c , -NR ^a S (O) ₂ NR ^b R ^c , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -S (O) NR ^b R ^c and -S ( O) ₂ NR ^b R ^c independently selected from, wherein each R ^a , R ^b , R ^c and R ^d are independently (i) hydrogen; (ii) C ₁ -C ₈ alkyl, C _{2 to} C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl or heterocyclyl, each of one or more, and in one embodiment 1, 2, 3 or 4 (Optionally substituted with the substituent Q ^a ) or (iii) R ^b and R ^c together with the N atom to which they are attached, one or more, in one implementation In the form a heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents Q ^a ;
Where each Q ^a is (a) oxo, cyano, halogen and nitro; (b) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl , C ₆ -C ₁₀ aryl, heteroaryl and heterocyclyl; and (c) -C (O) R ^f , -C (O) OR ^f , -C (O) NR ^g R ^h , -C (NR ^f ) NR ^{g R h, -OR f, -OC} (O) R f, -OC (O) OR f, -OC (O) NR g R h, -OC (= NR f) NR g R h, -OS (O ) R ^f , -OS (O) ₂ R ^f , -OS (O) NR ^g R ^h , -OS (O) ₂ NR ^g R ^h , -NR ^g R ^h , -NR ^f C (O) R ^k , ^{-NR f C (O) OR k} , -NR f C (O) NR g R h, -NR f C (= NR ^{) NR g R h, -NR f} S (O) R k, -NR f S (O) 2 R k, -NR f S (O) NR g R h, -NR f S (O) 2 NR g R ^{h, -SR f, -S (O} ) R f, -S (O) 2 R f, independently from the group consisting of -S (O) ^NR g ^{R h} and _{^{-S (O) 2 NR g R}} h Where each R ^f , R ^g , R ^h and R ^k are independently (i) hydrogen; (ii) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C _{8 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 6 _{-C 10} aryl, heteroaryl and heterocyclyl; or (iii) ^{R g} and ^{R h} are, together with the N atom to which they are attached a heterocyclyl Form a)
Or a single enantiomer, racemic mixture, diastereomeric mixture or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  In another embodiment, herein, Formula (D):

(Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , R ^L , L ¹ , L ² , m, n and i are each as defined herein)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof; in one embodiment, R ³ is a heterocyclyl compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; (Which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is a 4, 5 or 6 membered heterocyclyl ( Each of which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholino or thiomorpholino, each of which is optionally substituted with one or more substituents Q as defined herein; In another embodiment, ^{R 3} is 3,3-dimethyl azetidinyloxyimino or 1,1-oxidothiomorpholino.

  In another embodiment, herein, Formula (E):

(Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , R ^L , L ¹ , L ² , m, n and i are each as defined herein)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof; in one embodiment, R ³ is a heterocyclyl compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; (Which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is a 4, 5 or 6 membered heterocyclyl ( Each of which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholino or thiomorpholino, each of which is optionally substituted with one or more substituents Q as defined herein; In another embodiment, ^{R 3} is 3,3-dimethyl azetidinyloxyimino or 1,1-oxidothiomorpholino.

In one embodiment, in Formula (C), (D) or (E):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl (each of which is optionally substituted with one or more substituents Q) Selectively substituted);
L ² is a single bond or -C (O)-;
R ¹ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ³ is (a) cyano; (b) heterocyclyl, which is optionally substituted with one or more substituents Q; or (c) -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , -OR ^1a or -NR ^1a S (O) ₂ R ^1d ;
Each R ⁴ is independently hydrogen or C ₁ -C ₈ alkyl, wherein the alkyl is optionally substituted with one or more substituents Q; or two R ⁴ groups are Together with the C atom to which it is attached, form a C ₃ -C ₁₀ cycloalkyl, which is optionally substituted with one or more substituents Q;
R ⁵ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in Formula (C), (D) or (E):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl (each of which is optionally selected with one or more substituents Q Are substituted);
L ² is a single bond or -C (O)-;
R ¹ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ³ is (a) cyano; (b) a 4, 5 or 6 membered heterocyclyl, each of which is optionally substituted with one or more substituents Q); or (c) —NR ^1b R ^1c , -NR ^1a C (O) R ^1d , -OR ^1a or -NR ^1a S (O) ₂ R ^1d ;
Each R ⁴ is independently hydrogen or C ₁ -C ₈ alkyl, wherein the alkyl is optionally substituted with one or more substituents Q; or two R ⁴ groups are Together with the C atom to which it is attached, form a C ₃ -C ₁₀ cycloalkyl, which is optionally substituted with one or more substituents Q;
R ⁵ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in Formula (C), (D) or (E):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl (each of which is optionally substituted with one or more substituents Q) Selectively substituted);
L ² is a single bond or -C (O)-;
R ¹ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ³ is (a) cyano; (b) azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino or thiomorpholino, each of which is optionally substituted with one or more substituents Q); or (c And -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , -OR ^1a or -NR ^1a S (O) ₂ R ^1d ;
Each R ⁴ is independently hydrogen or C ₁ -C ₈ alkyl, wherein the alkyl is optionally substituted with one or more substituents Q; or two R ⁴ groups are Together with the C atom to which it is attached, form a C ₃ -C ₁₀ cycloalkyl, which is optionally substituted with one or more substituents Q;
R ⁵ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in Formula (C), (D) or (E):
L ¹ is hydrogen or -C (O) R ² , wherein R ² is C ₁ -C ₈ alkyl or C ₃ -C ₁₀ cycloalkyl (each of which is optionally substituted with one or more substituents Q) Selectively substituted);
L ² is a single bond or -C (O)-;
R ¹ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ³ is (a) cyano; (b) azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino or thiomorpholino, each of which is optionally substituted with one or more substituents Q); or (c And -NR ^1b R ^1c , -NR ^1a C (O) R ^1d , -OR ^1a or -NR ^1a S (O) ₂ R ^1d ;
Each R ⁴ is independently hydrogen or C ₁ -C ₈ alkyl, wherein the alkyl is optionally substituted with one or more substituents Q; or two R ⁴ groups are Together with the C atom to which it is attached, form a C ₃ -C ₁₀ cycloalkyl, which is optionally substituted with one or more substituents Q;
R ⁵ is halogen or C ₁ -C ₈ alkyl, said alkyl being optionally substituted with one or more substituents Q;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;
Each R ^1a , R ^1b , R ^1c , R ^1d and Q is as defined herein.

In another embodiment, in Formula (C), (D) or (E):
L ¹ is hydrogen or —C (O) R ² , wherein R ² is isopropyl, cyclopropyl or cyclobutyl;
L ² is a single bond or -C (O)-;
R ¹ is fluoro, chloro or methyl;
R ³ is, (a) cyano, cyano-methylphenylamino, 3,3,3-trifluoro propanamide, methoxy or cyclopropane sulfonamide; or (b) azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl, morpholino, piperazinyl or thiomorpholino (These are each optionally substituted with one or two substituents Q, wherein each Q is independently oxo, cyano, hydroxyl or C ₁ -C ₈ alkyl, Alkyl is optionally substituted with one or more substituents Q ^a as defined herein;
Each R ⁴ is independently hydrogen or methyl; or two R ⁴ groups together with the C atom to which they are attached form cyclopropyl;
R ⁵ is fluoro or methyl;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;

In another embodiment, in Formula (C), (D) or (E):
L ¹ is hydrogen or —C (O) R ² , wherein R ² is isopropyl, cyclopropyl or cyclobutyl;
L ² is a single bond or -C (O)-;
R ¹ is chloro or methyl;
R ³ is (a) cyano, cyanomethylphenylamino, 3,3,3-trifluoropropanamide, methoxy or cyclopropane sulfonamide; or (b) azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl, morpholino, piperazinyl or thiomorpholino (These are each optionally substituted with one or two substituents Q, wherein each Q is independently oxo, cyano, hydroxyl or methyl);
Each R ⁴ is independently hydrogen or methyl; or two R ⁴ groups together with the C atom to which they are attached form cyclopropyl;
R ⁵ is fluoro or methyl;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;

In another embodiment, in Formula (C), (D) or (E):
L ¹ is hydrogen;
L ² is a single bond or -C (O)-;
R ¹ is fluoro, chloro or methyl;
R ³ is cyano, 2-cyanomethylphenylamino, 3,3,3-trifluoropropanamide, 3-hydroxypyrrolidin-1-yl, (R) -3-hydroxypyrrolidin-1-yl, (S) -3 -Hydroxypyrrolidin-1-yl, piperidin-1-yl, 4-cyanopiperidin-1-yl, morpholin-4-yl, 4-methyl-piperazin-1-yl, 1,1-dioxide thiomorpholine-4- I, methoxy, 3, 3-dimethylazetidin-1-yl or cyclopropane sulfonamide;
Each R ⁴ is independently hydrogen or methyl; or two R ⁴ groups together with the C atom to which they are attached form cyclopropyl;
R ⁵ is fluoro or methyl;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;

In yet another embodiment, in Formula (C), (D) or (E):
L ¹ is —C (O) R ² wherein R ² is isopropyl, cyclopropyl or cyclobutyl;
L ² is a single bond or -C (O)-;
R ¹ is fluoro, chloro or methyl;
R ³ is cyano, 2-cyanomethylphenylamino, 3,3,3-trifluoropropanamide, 3-hydroxypyrrolidin-1-yl, (R) -3-hydroxypyrrolidin-1-yl, (S) -3 -Hydroxypyrrolidin-1-yl, piperidin-1-yl, 4-cyanopiperidin-1-yl, morpholin-4-yl, 4-methyl-piperazin-1-yl, 1,1-dioxide thiomorpholine-4- I, methoxy, 3, 3-dimethylazetidin-1-yl or cyclopropane sulfonamide;
Each R ⁴ is independently hydrogen or methyl; or two R ⁴ groups together with the C atom to which they are attached form cyclopropyl;
R ⁵ is fluoro or methyl;
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 or 1;
i is an integer of 0 or 1;

  In yet another embodiment, Formula (F):

(Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , L ² , m, n and i are each as defined herein)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof; in one embodiment, R ³ is a heterocyclyl compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; (Which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is a 4, 5 or 6 membered heterocyclyl ( Each of which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholino or thiomorpholino, each of which is optionally substituted with one or more substituents Q as defined herein; In another embodiment, ^{R 3} is 3,3-dimethyl azetidinyloxyimino or 1,1-oxidothiomorpholino.

  In another embodiment, herein, Formula (G):

(Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , L ² , m, n and i are each as defined herein)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof; in one embodiment, R ³ is a heterocyclyl compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; (Which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is a 4, 5 or 6 membered heterocyclyl ( Each of which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholino or thiomorpholino, each of which is optionally substituted with one or more substituents Q as defined herein; In another embodiment, ^{R 3} is 3,3-dimethyl azetidinyloxyimino or 1,1-oxidothiomorpholino.

  In yet another embodiment, Formula (H):

(Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , L ² , m, n and i are each as defined herein)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof; in one embodiment, R ³ is a heterocyclyl compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; (Which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is a 4, 5 or 6 membered heterocyclyl ( Each of which is optionally substituted with one or more substituents Q as defined herein); in another embodiment, R ³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholino or thiomorpholino, each of which is optionally substituted with one or more substituents Q as defined herein; In another embodiment, ^{R 3} is 3,3-dimethyl azetidinyloxyimino or 1,1-oxidothiomorpholino.

  In yet another embodiment, as described herein, Formula (I):

(In the formula:
L ¹ is selected from hydrogen and -C (O) R ² ;
L ² is a single ^{bond, -O -, - NR 6 -} , - C (O) -, - C (O) O -, - OC (O) -, - CONR 6 -, - NR 6 CO -, - _{S (O) 2 -, -} NR 6 SO 2 - and -S _(O) 2 NR ⁶ - is selected from;
m is an integer selected from 0 to 6;
n is a selected integer of 0, 1, 2 or 3;
i is a selected integer of 0, 1, 2, 3 or 4;
R ¹ is independently at each occurrence halogen, alkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, acyl, thio, thioalkoxy, thioaryloxy, thioheteroaryloxy, acylamino, alkoxy, amino, alkylamino, Selected from arylamino, heteroarylamino, amido, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, sulfonyl, carboxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
R ² is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl;
R ³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, hetero Selected from arylthio, cyano, hydroxy, -OR ⁷ , -N (R ⁶ ) ₂ , -COR ⁷ and -CON (R ⁶ ) ₂ ;
R ⁴ in each occurrence independently is hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, acyl, acylamino, carboxy, cyano, amido, amino, alkylamino, arylamino, heteroarylamino, alkoxy, aryloxy, Selected from heteroaryloxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl (optionally substituted with 1 to 4 R ⁸ if possible); or 2 R ^{4 taken} together form a 3 to 9 membered ring, said ring optionally comprising 1 to 4 heteroatoms independently selected from N, O and S And is optionally substituted with 1 to 5 R ⁸ ;
R ⁵ is independently at each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, acyl, thio, thioalkoxy, thioaryloxy, thioheteroaryloxy, acylamino, alkoxy, amino, alkyl Selected from amino, arylamino, heteroarylamino, amido, sulfinyl, sulfonyl, aminosulfonyl, sulfonyl, carboxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
R ⁶ is independently at each occurrence selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or alternatively, two R ⁶ together form 3 to 9 Membered ring, which optionally comprises 1 to 4 heteroatoms independently selected from N, O and S, and optionally 1 to 5 R ⁸ Selectively substituted;
R ⁷ is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
R ⁸ independently at each occurrence of alkyl, alkenyl, alkynyl, haloalkyl, acyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, amino, cyano , nitro, ^{carboxy, -C (= O) OR 9} , trifluoromethoxy, hydroxyl, ^{thiol, -OR 9, -SR 9, -C} (= O) NR a R b, -NR a R b, -S ( _{^{O) 2 NR a R b,}} -S (O) 2 R 9, is selected from ^{-NR a C (= O) R} 9 and -OC (= O) ^{R 9;}
R ⁹ in each occurrence is independently hydrogen, C ₁ -C ₆ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R ^a and R ^b are each independently hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or alternatively, R ^a and R ^b together optionally, optionally Form a substituted 3 to 6 membered ring, said ring optionally comprising 1 or 2 heteroatoms independently selected from N, O and S)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In one embodiment, in Formula (I):
L ¹ is selected from hydrogen and -C (O) R ² ;
L ² is a single ^{bond, -O -, - NR 6 -} , - C (O) -, - C (O) O -, - OC (O) -, - CONR 6 -, - NR 6 CO -, - _{S (O) 2 -, -} NR 6 SO 2 - and -S _(O) 2 NR ⁶ - is selected from;
m is an integer selected from 0 to 6;
n is a selected integer of 0, 1, 2 or 3;
i is a selected integer of 0, 1, 2, 3 or 4;
R ¹ in each occurrence independently is halogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, cyano, hydroxyl, nitro, acyl, thio, C ₁ -C ₈ thio Alkoxy, C ₆ -C ₁₀ thioaryloxy, thioheteroaryloxy, acylamino, C ₁ -C ₈ alkoxy, amino, C ₁ -C ₈ alkylamino, C ₆ -C ₁₀ arylamino, heteroarylamino, amide, C ₁ -C _{8 alkylsulfinyl,} C 1 -C ₈ alkylsulfonyl, aminosulfonyl, sulfonyl, _carboxy, C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl _-C 1 -C ₈ alkyl, heterocyclyl, heterocyclyl -C ₁ -C _{8 alkyl,} C 6 _{-C 10 aryl,} C 6 _{-C 10} arylene Selected from ル -C ₁ -C ₈ alkyl, heteroaryl and heteroaryl-C ₁ -C ₈ alkyl;
R ² is selected from substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl and substituted or unsubstituted heterocyclyl;
R ³ is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₈ alkyl, C ₃ -C _{10 cycloalkyl,} C 3 _{-C 10} cycloalkyl _-C 1 -C ₈ alkyl, heteroaryl, heteroaryl _-C 1 -C ₈ alkyl, heterocyclyl, heterocyclyl _-C 1 -C _{8 alkyl,} C 1 -C _{8 alkoxy,} C 6 _{-C 10} aryloxy, _{heteroaryloxy,} C 1 -C _{8 alkylthio,} C 6 _{-C 10} arylthio, heteroarylthio, cyano, _{^{hydroxyl, -OR 7, -N (R 6}} ) 2, -COR Selected from ⁷ and -CON (R ⁶ ) ₂ ;
R ⁴ in each occurrence independently is hydrogen, hydroxyl, halogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, acyl, acylamino, carboxy, cyano, amido, amino, C ₁ -C ₈ alkylamino, C ₆ -C ₁₀ arylamino, heteroarylamino, C ₁ -C ₈ alkoxy, C ₆ -C ₁₀ aryloxy, heteroaryloxy, C ₃ -C ₁₀ cycloalkyl, C _3- Selected from C ₁₀ cycloalkyl-C ₁ -C ₈ alkyl, heterocyclyl, C ₆ -C ₁₀ aryl and heteroaryl (optionally substituted with 1 to 4 R ⁸ where possible) or; alternatively, two R ⁴ is forms a ring of 3-9 members together, said ring optionally, N, or O, and S Are those independently containing from 1 to 4 heteroatoms selected are optionally substituted with 1-5 R ^8;
R ⁵ is independently at each occurrence hydrogen, halogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, cyano, hydroxyl, nitro, acyl, thio, C ₁ -C _{8 thioalkoxy,} C 6 _{-C 10} thioaryloxy, thioheteroaryloxy, _acylamino, C 1 -C ₈ alkoxy, _amino, C 1 -C _{8 alkylamino,} C 6 _{-C 10} arylamino, heteroarylamino, amido , Sulfinyl, sulfonyl, aminosulfonyl, sulfonyl, carboxy, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl-C ₁ -C ₈ alkyl, heterocyclyl, heterocyclyl -C ₁ -C ₈ alkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₈ alkyl, hetero Selected from: reel and heteroaryl-C ₁ -C ₈ alkyl;
R ⁶ is independently in each occurrence hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclyl, C ₆ -C ₁₀ aryl And heteroaryl, or alternatively, two R ⁶ together form a 3-9 membered ring, said ring optionally being independently from N, O and S Comprising 1 to 4 selected heteroatoms, optionally substituted with 1 to 5 R ⁸ ;
R ⁷ is selected from C ₃ -C ₁₀ cycloalkyl, heterocyclyl, C ₆ -C ₁₀ aryl and heteroaryl;
R ⁸ independently in each occurrence C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, acyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, heterocyclyl, heterocyclyl _-C 1 -C _{8 alkyl,} C 6 _{-C 10 aryl,} C 6 _{-C 10} aryl _-C 1 -C ₈ alkyl, heteroaryl, heteroaryl _-C 1 -C ₈ alkyl, halogen, amino, cyano, nitro, ^{carboxy, -C (= O) OR 9} , trifluoromethoxy, hydroxyl, ^{thiol, -OR 9, -SR 9, -C} (= O) NR a R b, - _{^{NR a R b, -S (O}} ) 2 NR a R b, -S (O) 2 R 9, selected from ^{-NR a C (= O) R} 9 and -OC (= O) ^{R 9} It is;
R ⁹ independently at each occurrence is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, heterocyclyl, C ₆ -C ₁₀ aryl or heteroaryl;
R ^a and R ^b are each independently hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or alternatively, R ^a and R ^b together optionally Forming a substituted 3 to 6 membered ring, said ring optionally comprising one or two heteroatoms independently selected from N, O and S.

  In one embodiment, herein:

And their isotopic variants; and pharmaceutically acceptable salts, solvates and prodrugs thereof.

  In another embodiment, as used herein:

And their isotopic variants; and pharmaceutically acceptable salts, solvates and prodrugs thereof.

  In yet another embodiment, as used herein:

And their isotopic variants; and pharmaceutically acceptable salts, solvates and prodrugs thereof.

  The compounds provided herein are intended to encompass all possible stereoisomers, unless a specific stereochemical configuration is specified. When the compounds provided herein contain an alkenyl group, the compounds may exist as one or a mixture of cis / trans (or Z / E) geometric isomers. When structural isomers are interconvertible, the compounds may exist as one tautomer or a mixture of tautomers. This may be, for example, the proton tautomeric form of said compound containing an imino, keto or oxime group; it may be the so-called valence tautomeric form of said compound containing an aromatic moiety. As a result, one type of compound may exhibit more than one type of isomerism.

  The compounds provided herein may be enantiomerically pure, eg, one enantiomer or one diastereomer, and a stereoisomer mixture, eg, an enantiomer mixture, eg, a racemate of two enantiomers It may be a mixture; or a mixture of two or more diastereomers. Thus, one of ordinary skill in the art will recognize that administration of a compound in the (R) form is equivalent to administration of the compound in the (S) form for compounds that are epimerized in vivo. Conventional procedures for the preparation / isolation of individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from chiral starting materials or resolution of enantiomeric mixtures, eg chiral chromatography After recrystallization, resolution, formation of diastereomeric salts or derivatization of diastereomeric adducts, separation may be mentioned.

  Where the compounds provided herein contain an acidic or basic moiety, this may be provided as a pharmaceutically acceptable salt. Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed .; Wiley-VCH and VHCA: See Zurich, Switzerland, 2002 Of.

  Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, Benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid , Cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptone Acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglucose Acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)- L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid Oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, sugar acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, There may be mentioned tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a salt of camphorsulfonic acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, phosphoric acid or sulfuric acid of the compound. It is.

  Suitable bases for use in the preparation of pharmaceutically acceptable salts, such as, but not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide; and organic Bases such as primary, secondary, tertiary and quaternary aliphatic and aromatic amines, such as L-arginine, benetamine, benzathine, choline, dianol, diethanolamine, diethylamine, dimethylamine, diamine Propylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamin, 1H-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -Morpholine Methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amine, triethanolamine, trimethylamine, triethylamine, N-methyl-D- Glucamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol and tromethamine.

  Also, the compounds provided herein can be provided as prodrugs, which are functional derivatives of the compound (e.g., of Formula I), which are readily convertible in vivo into the parent compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. For example, prodrugs may be biocompatible by oral administration, but not the parent compound. Also, prodrugs can be of improved solubility in pharmaceutical compositions over the parent compound. Prodrugs can be converted to the parent drug by a variety of mechanisms, for example, by enzymatic processes and hydrolysis by metabolism. Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. In Design of Biopharmaceutical Properties through Prodrugs and Analogs; Roche Ed., APHA Acad. Pharm. Sci .: 1977; Gangwar et al., Des. Prop. Prodrugs Analogs, 1977, 409-421; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Design: Fact or Fantasy; Jolles et al. Eds .; Academic Press: London, 1984; pp 47-72; Design of Prodrugs; Bundgaard et al. Eds .; Elsevier: 1985; Fleisher et al., Methods Enzymol. 112, 360-381; Stella et al., Drugs 1985, 29, 455-473; Bioreversible Carriers in Drug Design, Theory and Application; Roche Ed .; APHA Acad. Pharm. Sci .: 1987; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143- 53; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-3 8; Nathwani and Wood, Drugs 1993, 45, 866-94; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Gaignault et al., Pract. Med. Chem. 1996 Neuron, Clin. Neuropharmacol. 1997, 20, 1-12; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; Tan et al., Adv. Drug Delivery Rev. Drug et al., 1999, 39, 117-151; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Han et al., AAPS Pharmsci. 2000, 2, 1-11; Asgharnejad in Transport Processes in Pharmaceutical Systems; Amidon et al., Eds .; Marcell Dekker: 2000; pp 185-218; Sinha et al., Pharm. Res. 2001, 18, 557- 564; Anand et al., Expert Opin. Biol. Ther. 2002, 2, 607-620; Rao, Resonace 2003, 19-27; Sloan et al., Med. Res. Rev. 2003, 23, 763-793; Patterson et al., Curr. Pharm. Hu, IDrugs 2004, 7, 736-742; Robinson et al., Proc. Natl. Acad. Sci. USA 2004, 101, 14527-14532; Erion et al., J. Des. Pharmacol. Exp. Ther. 2005, 312, 554-560; Fang et al., Curr. Drug Discov. Technol. 2006, 3, 211-224; Stanczak et al., Pharmacol. Rep. 2006, 58, 599-. Sloan et al., Pharm. Res. 2006, 23, 2729-2747; Stella et al., Adv. Drug Deliv. Rev. 2007, 59, 677-694; Gomes et al., Molecules 2007, 12, 2484 Krafz et al., ChemMedChem 2008, 3, 20-53; Rautio et al., AAPS J. 2008, 10, 92-102; Rautio et al., Nat. Rev. Drug. Discov. 2008, 7, Pavan et al., Molecules, 2008, 13, 1035-1065; Sandros et al., Molecules 2008, 13, 1156-1178; Singh et al., Curr. Med. Chem. 2008, 15, 1802- 1826; Onishi et al., Molecules, 2008, 13, 2136-2155; Huttunen et al., Curr. Med. Chem. 2008, 15, 2346-2365; and Serafin et al., Min. i Rev. Med. Chem. 2009, 9, 481-497.

Synthetic Methods The compounds provided herein may be prepared, isolated or obtained by any method known to one skilled in the art.

For example, the compounds provided herein can be prepared according to Scheme I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L ² , m, n and i are each as defined herein. Can be prepared as shown in The conversion of the carboxylic acid of compound I-1 to the Boc protected amine of compound I-2 is carried out using DPPA in the presence of a base such as triethylamine. The Boc group of compound I-2 is deprotected using trifluoroacetic acid and then acylated to form compound I-3. Catalyst with pinacol borate I-4 and bromide I-3 _{(e.g., Pd (dppf) 2 Cl 2} ) by Suzuki coupling in the presence of Compound I-6 obtained.

Also, the compounds provided herein can be prepared according to Scheme II, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L ² , m, n and i are each as defined herein. Can be prepared as shown in Treatment with B ₂ (pin) ₂ and Pd (dppf) ₂ Cl ₂ as catalysts with bromides I-3 and I-5 gives compounds I-6.

^{_{a) DPPA / Et 3 N;}} b) TFA; c) R 2 C (O) Cl / Et 3 N; d) Pd (dppf) Cl 2 / K 2 CO 3.

e) B ₂ (pin) ₂ / Pd (dppf) Cl ₂ .
The starting materials used in the synthesis of the compounds provided herein are either commercially available or those which can be readily prepared. For example, the synthesis of pinacol borate I-4 can be obtained, for example, in US Pat. No. 8,853,240; the disclosure of which is incorporated herein by reference in its entirety.

Pharmaceutical Compositions In one embodiment, the compounds provided herein as (i) active ingredients herein, such as a compound of any one of Formulas (A)-(I) or one of its enantiomers, A pharmaceutical composition comprising a racemic mixture, a mixture of diastereomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and (ii) a pharmaceutically acceptable excipient. Do.

  Suitable pharmaceutically acceptable excipients are well known to those skilled in the art. Whether a particular excipient is suitable for incorporation into the pharmaceutical composition provided herein depends on various factors well known in the art, including but not limited to the mode of administration. For example, pharmaceutical compositions of oral dosage forms, such as tablets, may contain excipients not suitable for use in parenteral dosage forms. Also, the suitability of specific excipients may also depend on the specific active ingredients in the pharmaceutical composition. For example, degradation of the active ingredient may be accelerated by excipients such as lactose. Active ingredients containing primary or secondary amines are particularly susceptible to such accelerated degradation. Thus, provided herein are pharmaceutical compositions that contain only small amounts of lactose or other mono- or di-saccharides (if any). As used herein, the term "lactose free" means that the amount of lactose (if any) present substantially increases the degradation rate of the active ingredient in the pharmaceutical composition provided herein. It means that it is not enough.

  The compounds provided herein may be administered alone or in combination with one or more other compounds provided herein. A compound provided herein, eg, a compound of any one of Formulas (A)-(I) or one of its enantiomers, racemic mixture, diastereomeric mixture or isotopic variant; or a pharmaceutically acceptable thereof Pharmaceutical compositions, including the resulting salts, solvates or prodrugs, can be formulated into various dosage forms for oral, parenteral and transsurface administration. Also, the pharmaceutical composition may be in a controlled release dosage form such as delayed release, extended release, sustained release, sustained release, pulsatile release, controlled release, accelerated release, rapid release, targeted release, programmed release and intragastric It may be formulated as a depot dosage form. Such dosage forms can be prepared according to conventional methods and procedures known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed .; Rathbone et al., Eds .; CRC Press: 2008.

  In one embodiment, (i) a compound provided herein, such as a compound of any one of Formulas (A)-(I) or one of its enantiomers, racemic mixture, diastereomeric mixture or isotopic variant Or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable salt, solvate or prodrug thereof; and (ii) a pharmaceutically acceptable excipient Pharmaceutical compositions in dosage form for oral administration are provided, including.

  In another embodiment, (i) a compound provided herein, such as a compound of any one of Formulas (A)-(I) or one of its enantiomers, racemic mixture, diastereomeric mixture or isotope Or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable salt, solvate or prodrug thereof; and (ii) a pharmaceutically acceptable excipient and And provides a pharmaceutical composition in dosage form for parenteral administration.

  In yet another embodiment, (i) a compound provided herein, such as a compound of any one of formulas (A) to (I) or one of its enantiomers, racemic mixture, diastereomeric mixture or isotope Or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable salt, solvate or prodrug thereof; and (ii) a pharmaceutically acceptable excipient And provides a pharmaceutical composition in a dosage form for transsurface administration.

  The pharmaceutical compositions provided herein may be provided in unit dosage form or in multiple dosage forms. Unit-dose forms, as used herein, refer to physically discrete units suitable for administration to a subject and packaged individually as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, together with the required pharmaceutical excipient (s). Examples of unit dose forms include ampoules, syringes and individually packaged tablets and capsules. For example, a unit dose of 100 mg contains about 100 mg of the active ingredient in a packaged tablet or capsule. The unit dosage form may be administered in divided or multiple doses. Repeated dosage forms are multiple identical unit dosage forms administered in individual unit dosage forms packaged in a single container. Examples of multiple-dose forms include vials, bottled tablets or capsules or bottles of pint unit or gallon units.

  The pharmaceutical compositions provided herein may be administered once or multiple times spaced apart. The exact dosage and duration of treatment may vary with the age, weight and condition of the subject to be treated, experienced using known test protocols or by extrapolation from in vivo or in vitro tests or diagnostic data It will be understood that it can be determined Furthermore, for any particular individual, the specific dosage regimen will be adjusted over time according to the individual's needs and the professional judgment of the person responsible for administering the pharmaceutical composition or the administration supervisor. It will be understood that

A. Oral Administration The pharmaceutical compositions provided herein for oral administration can be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, translingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strip packaging, troches, lozenges, lozenges, troches, cachets, pellets, pharmaceuticals Chewing gum, bulk powder, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkle capsules, elixirs and syrups. In addition to the active ingredient (s), the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, such as, but not limited to, binders, fillers, diluents, disintegrants, wetting Agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, flavors, emulsifiers, suspending agents and dispersants, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide Sources may be included.

The binder or granulating agent imparts to the tablet cohesiveness to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch and pregelatinized starch (e.g. STARCH 1500 < ^(R) >);gelatin; sugars such as sucrose, glucose, dextrose, molasses And lactose; natural and synthetic gums such as acacia, alginic acid, alginate, irish moss extract, panwar gum, gati gum, mucus of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth and guar gum; celluloses such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose Calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose, e.g., AVICEL ^(TM) CL-611, AVICEL ^{(registered trademark)} PH -101, AVICEL ^{(registered trademark)} PH-102, AVICEL ^{(registered trademark)} PH-103, AVICEL ^{(registered trademark)} PH-105, AVICEL ^{(registered trademark)} PH-112, AVICEL ^{(registered trademark)} PH-113, AVICEL ^{( R)} PH-200, AVICEL ^{(registered trademark)} PH-301, AVICEL ^{(registered trademark)} PH-302, AVICEL ^(TM) RC-501, AVICE ^(R) RC-581 and AVICEL ^(R) RC-591; and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The amount of binder or filler in the pharmaceutical compositions provided herein will vary depending on the type of formulation and will be readily appreciated by one skilled in the art. The pharmaceutical compositions provided herein may contain about 50 to about 99% by weight of a binder or filler.

  Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Properties that allow certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, to disintegrate by chewing in the mouth, for some compressed tablets, when present in sufficient amounts May be granted. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein will vary depending on the type of formulation and will be readily appreciated by those skilled in the art. The pharmaceutical compositions provided herein may contain about 10 to about 99% by weight of a diluent.

  Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acids; gums such as guar gum and Veegum HV; Cross-linked polymers such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch and alpha Clay; align; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and will be readily appreciated by those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% or about 1 to about 5% (by weight) of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; Talc; hydrogenated vegetable oil such as peanut oil, cotton seed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate (laureate); agar; starch; Silica gel, such as AEROSIL ^(R) 200 and CAB-O-SIL ^(R) ; and mixtures thereof. The amount of lubricant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and will be readily appreciated by those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL < ^(R) > and asbestos free talc. Suitable colorants include, but are not limited to, any of the approved certified water soluble FD & C dyes, water insoluble FD & C dyes suspended on alumina hydrate, color lakes and mixtures thereof. Color lakes are insoluble forms of water-soluble dyes formed by adsorbing water-soluble dyes onto hydrated oxides of heavy metals. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants such as fruits, and blends of synthetic compounds that provide a pleasing taste, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN ^(R) 20), polyoxyethylene sorbitan monooleate 80 (TWEEN (Registered trademark) 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic add, sodium benzoate and alcohols. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol and syrup. Suitable non-aqueous liquids for use in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include but are not limited to citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

It will be appreciated that many excipients may perform multiple functions even in the same formulation.
The pharmaceutical compositions provided herein for oral administration may be provided as compressed tablets, powder tablets, chewable lozenges, fast dissolving tablets, coated tablets, enteric coated tablets or dragee or film coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine and thus protects the active ingredient (s) from the acidic environment of the stomach. is there. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which cover the unpleasant taste or smell, and the active ingredient (s) or excipients or excipients (one or more) in the tablet. ) Can be useful to protect from oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Nucleated tablets are compressed tablets made by more than one compression cycle, such as, for example, layered tablets and press-coated or dry-coated tablets.

  The tablet dosage form may be alone from the active ingredient (s) in powdered, crystalline or granular form, or one or more excipients as described herein, eg, binders, disintegrants It may be prepared in combination with controlled release polymers, lubricants, diluents and / or colorants. Flavoring or sweetening agents are particularly useful in the formation of chewable tablets or lozenges.

  The pharmaceutical compositions provided herein for oral administration may be provided as soft or hard capsules, which may be made from gelatin, methyl cellulose, starch or calcium alginate. Gelatin hard capsules, also known as dry-filled capsules (DFCs), are coated from one onto the other, thus from two sections completely encapsulating the active ingredient (s) Become. Elastic soft capsules (SEC) are flexible spherical shells, for example gelatin shells, which are plasticized by the addition of glycerin, sorbitol or similar polyols. The flexible gelatin shell may contain a preservative to inhibit the growth of microorganisms. Suitable preservatives are those described herein, such as methyl- and propyl-paraben and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein may be enclosed in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. Capsules may also be coated as known to those skilled in the art to control or sustain dissolution of the active ingredient (s).

  The pharmaceutical compositions provided herein for oral administration may be provided in liquid or semisolid dosage forms such as emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid, which may be oil-in-water or water-in-oil. The emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. For aqueous alcoholic solutions pharmaceutically acceptable acetals of lower alkyl aldehydes, such as di (lower alkyl) acetals, such as acetaldehyde diethyl acetal; and water miscible solvents having one or more hydroxyl groups, such as propylene Glycol and ethanol can be included. Elixirs are clear, sweet, hydro-alcoholic solutions. Syrups are aqueous concentrates of sugars such as sucrose and may also contain preservatives. In liquid dosage forms, for example, solutions in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier such as water to be conveniently metered for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, active ingredients provided herein and dialkylated mono- or poly-alkylene glycols such as 1,2-dimethoxymethane, diglyme, triglyme , Tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where the numbers "350", "550," and "750" are approximate numbers of the respective polyethylene glycols) Include those having an average molecular weight (referred to as M _n ). Such dosage forms further include one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine Lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates may be included.

  The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

  The pharmaceutical compositions provided herein for oral administration may be provided as non-effervescent or effervescent granules or powders and may be reconstituted into a liquid dosage form. Pharmaceutically acceptable excipients used for non-effervescent granules or powders may include diluents, sweeteners and / or wetting agents. Pharmaceutically acceptable excipients used for effervescent granules or powders include organic acids and carbon dioxide sources.

Coloring agents and flavoring agents may be used in all dosage forms described herein.
Immediate release dosage form or controlled release dosage form, such as delayed release form, sustained release form, pulsatile release form, controlled release form, targeted release form and programmed, pharmaceutical compositions provided herein for oral administration It may be formulated as a release form.

B. Parenteral Administration The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein is intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical and subcutaneous administration Is included.

  The pharmaceutical compositions provided herein for parenteral administration may be in any dosage form suitable for parenteral administration, such as solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and injections. It can be formulated into solid forms suitable for solution or suspension in liquid form beforehand. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacology (see Remington: The Science and Practice of Pharmacy, supra).

  Pharmaceutical compositions for parenteral administration include one or more pharmaceutically acceptable excipients, such as, but not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial agents against the growth of microorganisms or Preservatives, stabilizers, solubility improvers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, frozen Protectants, lyophilizers, thickeners, pH adjusters and inert gases may be included.

  Suitable aqueous vehicles include, but are not limited to, water, saline, saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection and These include dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean Oils include medium chain triglycerides of coconut oil and palm kernel oil. Suitable water miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N, N-dimethylacetamide and dimethylsulfoxide are included.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial agents, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (eg benzethonium chloride), methyl And propyl-paraben and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin and dextrose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, for example sodium carboxymethylcellulose (celluose), hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable emulsifiers are those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering agents or chelating agents include but are not limited to EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin and sulfobutyl ether 7-β-cyclo Dextrin (CAPTISOL ^(R) ) is mentioned.

  When the pharmaceutical composition provided herein is formulated for administration in multiple doses, multiple doses of parenteral formulations must contain the antimicrobial agent at a bacteriostatic or bacteriostatic concentration. It does not. All parenteral formulations must be sterile as known and practiced in the art.

  In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile, soluble, dry preparation, such as a lyophilized powder or a tablet for injection, and is reconstituted with a vehicle prior to use. In another embodiment, the pharmaceutical composition is provided as a ready-made sterile suspension. In another embodiment, the pharmaceutical composition is provided as a sterile, insoluble dry preparation which is reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

  Immediate release dosage forms or controlled release dosage forms provided herein for parenteral administration such as delayed release forms, sustained release forms, pulsatile release forms, controlled release forms, targeted release forms and programs It may be formulated as a modified release form.

  The pharmaceutical compositions provided herein for parenteral administration may be formulated as suspensions, solid, semi-solid or thixotropic solutions for administration as an implanted depot. In one embodiment, the pharmaceutical composition provided herein is dispersed in a solid internal matrix, which is insoluble in body fluids but generally contains the active ingredient (s) in the pharmaceutical composition. It is surrounded by an outer polymer membrane that allows diffusion.

  Suitable internal matrices include, but are not limited to, polymethyl methacrylate, polybutyl-methacrylate, plasticized or non-plasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene Ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, crosslinked polyvinyl alcohol and partially hydrolyzed crosslinked polyvinyl acetate .

  Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, poly Vinyl chloride, vinyl chloride and vinyl acetate, copolymers of vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / vinyloxyethanol Copolymers may be mentioned.

C. Trans-Surface Administration The pharmaceutical compositions provided herein may be trans-surface administered to the skin, an opening or a mucous membrane. Transsurface administration, as used herein, may be transdermal (intradermal), transconjunctival, intracorneal, intraocular, transocular, transaural, transcutaneous, nasal, transvaginal, transurethral, transpulmonary and transpulmonary. Rectal administration is included.

  The pharmaceutical compositions provided herein may be in any dosage form suitable for topical or systemic effect, for example, for emulsion, solution, suspension, cream, gel, hydrogel, ointment Formulated as powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, ophthalmic solutions, sprays, suppositories, bandages and transdermal patches obtain. Also, the surface preparation of the pharmaceutical composition provided herein may include liposomes, micelles, microspheres, nanosystems and mixtures thereof.

  Pharmaceutically acceptable carriers and excipients suitable for use in the surface preparation provided herein include, but are not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial agents against the growth of microorganisms Or preservatives, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, Permeation enhancers, lyoprotectants, lyoprotectants, thickeners and inert gases are included.

Further, the pharmaceutical compositions, electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection may be administered, for example, topical by POWDERJECT ^(TM) and BIOJECT ^(TM).

  The pharmaceutical compositions provided herein may be provided in the form of ointments, creams and gels. Suitable vehicles for ointments include oily or hydrocarbon vehicles such as lard, benzoin-containing lard, olive oil, cottonseed oil and white petrolatum; emulsifying or absorbing vehicles such as hydrophilic petrolatum, hydroxystearin sulfate and hydrated lanolin; Water-removable vehicles such as hydrophilic ointments; vehicles for water-soluble ointments such as polyethylene glycols of various molecular weights; vehicles for emulsions (water-in-oil (W / O) emulsions or oil-in-water (O / W) Any of the emulsions), such as cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). Such vehicles are emollient but generally require the addition of antioxidants and preservatives.

  Suitable cream bases may be oil-in-water or water-in-oil. Suitable creaming vehicles may be water-washable, and may contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also referred to as the "inner" phase, which is generally composed of petrolatum and fatty alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic or amphoteric surfactant.

The gel is a semi-solid suspension system. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers such as carbomers, carboxypolyalkylenes and CARBOPOL ^(R); hydrophilic polymers such as polyethylene oxides, polyoxyethylene - polyoxypropylene copolymers and polyvinyl Alcohols; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. A dispersing agent such as an alcohol or glycerin may be added to prepare a uniform gel, or the gelling agent may be dispersed by attrition, mechanical mixing and / or stirring.

  The pharmaceutical composition provided herein can be used as a suppository, pessary, bougie, poultice or hap, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, suspension, tampon, It may be administered rectally, transurethral, vaginally or around the vagina in the form of a gel, foam, spray or enema. Such dosage forms can be prepared using conventional methods as described in Remington: The Science and Practice of Pharmacy, supra.

  Transrectal, transurethral and transvaginal suppositories are solid bodies for insertion into the opening of the body, which are solid at ambient temperature but melt or soften at body temperature, and the active ingredient (one or more ) Into the opening. Pharmaceutically acceptable carriers used for rectal and vaginal suppositories are bases or vehicles, for example, hardeners, which bring about a melting point around body temperature; and Antioxidants such as those described in Bi. And bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti wax, paraffin, white wax and yellow wax and fatty acids and hydrogels such as polyvinyl alcohol, Suitable mixtures of mono-, di- and triglycerides of hydroxyethyl methacrylate and polyacrylic acid are mentioned; also, combinations of different vehicles can be used. Transrectal and vaginal suppositories may be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

  The pharmaceutical compositions provided herein may be administered ocularly in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, solutions, gels, powders for ocular insertion and implantation.

  The pharmaceutical compositions provided herein may be administered to the respiratory tract intranasally or by inhalation. The pharmaceutical composition may be a pressurized container, a pump, a sprayer, an atomizer (eg, an atomizer using electrohydrodynamics to generate a fine mist) or a nebulizer alone or a suitable propellant, eg, 1,1 It can be provided in the form of an aerosol or solution for delivery with 1,2,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions may also be provided alone as a dry powder for insufflation, or together with an inert carrier such as lactose or phospholipids; and as nasal drops. For intranasal use, powders may include bioadhesive agents, such as chitosan or cyclodextrin.

  Solutions or suspensions for use in pressurized vessels, pumps, sprayers, atomizers or nebulizers, for dispersing, solubilizing or releasing ethanol, aqueous ethanol, or active ingredient (s) May be formulated to contain suitable alternative agents for prolonging; propellants as solvents; and / or surfactants such as sorbitan trioleate, oleic acid or oligolactic acid.

  The pharmaceutical compositions provided herein may be micronized to a size suitable for delivery by inhalation, for example, to about 50 μm or less or about 10 μm or less. Particles of such size are prepared using continuous methods known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. It can be done.

  Capsules, blisters and cartridges for use in an inhaler or insufflator are described herein as pharmaceutical compositions provided herein; suitable powder bases such as lactose or starch; and performance improvers such as l-leucine, It can be formulated to contain a powder mix of mannitol or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical compositions provided herein for inhaled / intranasal administration may further include suitable flavours, such as menthol and levomenthol; and / or sweeteners, such as saccharin and saccharin sodium.

  The pharmaceutical compositions provided herein for transsurface administration are formulated to be immediate release or controlled release, such as delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release. It can be done.

D. Modulated Release The pharmaceutical compositions provided herein may be formulated as a modified release dosage form. As used herein, the term "modulated release" means that the rate or location of release of the active ingredient (s) of the dosage form differs from that when the neat dosage form is administered by the same route Say Controlled release dosage forms include, but are not limited to, delayed release, extended release, sustained release, sustained release, pulsatile release, controlled release, accelerated release and rapid release, targeted release, programmed release, and gastric retention dosage form Can be mentioned. The pharmaceutical composition of the controlled release dosage form can be prepared by various controlled release devices and methods known to those skilled in the art, such as, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticle controlled release devices, ion exchange resins, It can be prepared using enteric coatings, multilayer coatings, microspheres, liposomes and combinations thereof. Alternatively, the release rate of the active ingredient (s) can also be controlled by altering the particle size and the polymorphism of the active ingredient (s).

  Examples of controlled release include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,763,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543. No. 5,639,476; No. 5,354,556; No. 5,639,480; No. 5,733,566; No. 5,739,108; , 891, 474; i5, 922, 356; i5, 958, 458; i5, 972, 891; i5, 980, 945; i. No. 6,045,830; No. 6,087,324; No. 6,113,943 No. 6,197,350; No. 6,248,363; No. 6,264,970; No. 6,267,981; No. 6,270,798; , 987; i.p. 6,376,461; i.p. 6,419,961; i.e. 6,589,548; i.6,613,358; i.6,623,756; No. 6,699,500; No. 6,793,936; No. 6,827,947; No. 6,902,742; No. 6,958,161; No. 7,255, No. 876; No. 7,416,738; No. 7,427,414; No. 7,485,322; Bussemer et al., Crit. Rev. Ther. Drug Carrier Syst. 2001, 18, 433 Modified-Release Drug Delivery Technology, supra; Maroni et al., Expert. Opin. Drug Deliv. 2005, 2, 855-871; Shi et al., Expert Opin. Drug Deliv. Polymers in Drug Delivery; Ijeoma et al., Eds .; CRC Press: 2006; Badawy et al., J. Pharm. Sci. 2007, 9, 948-959; Conway, Recent Pat. Formal Drug. Drug Deliv. Formul. 2008, 2, 1-8; Gazzaniga et al., Eur. J. Pharm. Biopharm. 2008, 68, 11-18; Nagarwal et al., Curr. Drug Deliv. 2008, 5, 282- Gallardo et al., Pharm. Dev. Technol. 2008, 13, 413-423; Chrzanowski, AAPS PharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech. 2008, 9, 639-645; Kalantzi et al. Formal. 2009, 3, 49-63; Saigal et al., Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70; and Roy et al., J. Control Release 2009 , 134, 74-80.

1. Matrix Controlled Release Devices The pharmaceutical compositions provided herein of controlled release dosage forms can be fabricated using matrix controlled release devices known to one of ordinary skill in the art. See Takada et al. In Encyclopedia of Controlled Drug Delivery; Mathiowitz Ed .; Wiley: 1999; Vol 2.

  In certain embodiments, the pharmaceutical compositions provided herein of the modified release dosage form are formulated with an erosive matrix device, which is a water-swellable, erosive or soluble polymer, such as Although not limited, synthetic polymers and naturally occurring polymers and derivatives such as polysaccharides and proteins.

Materials useful for forming the erosive matrix include, but are not limited to, chitin, chitosan, dextran, pullulan, gum agar, gum arabic, karaya gum, locust bean gum, gum tragacanth, carrageenan, gati gum, guar gum, xanthan gum, scleroglucan, starch (E.g. dextrin and maltodextrin), hydrophilic colloid (e.g. pectin), phosphatides (e.g. lecithin), alginates, propylene glycol alginate, gelatin, collagen, cellulosics (e.g. ethyl cellulose (EC), methyl ethyl cellulose (MEC) , Carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), Cellulose acetate (CA), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl acetate cellulose tri Melitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC)), polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid ester, polyacrylamide, polyacrylic acid, copolymer of ethacrylic acid or methacrylic acid (EUDRAGIT ^{(registered trademark) )),} poly (2-hydroxyethyl - methacrylate), polylactides, L- glutamic acid and ethyl -L- glutamate Copolymers, degradable lactic acid-glycolic acid copolymers, poly-D-(-)-3-hydroxybutyric acid and acrylic acid derivatives (eg butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate) And (trimethylaminoethyl) methacrylate chloride homopolymers and copolymers).

  In certain embodiments, the pharmaceutical compositions provided herein are or formulated with a non-erosion matrix device. The active ingredient (s) is dissolved or dispersed in an inert matrix and upon administration is released primarily by diffusion from the inert matrix. Materials suitable for use as non-erosion matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polychlorinated Vinyl, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / acid ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, vinyl chloride copolymer with ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichloromethane Hydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol Terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane and silicone carbonate copolymer; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone And partially hydrolyzed crosslinked polyvinyl acetate; and aliphatic compounds such as carnauba wax, microcrystalline wax and triglycerides.

  In matrix controlled release systems, the desired release kinetics may for example be the type of polymer used, the viscosity of the polymer, the particle size of the polymer and / or active ingredient (s), the active ingredient (s) to the polymer (s) It can be controlled by the ratio of the two or more other excipients or carriers in the composition.

  The pharmaceutical compositions provided herein of the modified release dosage form are prepared by methods known to the person skilled in the art, eg direct compression, dry or wet granulation followed by compression and melt granulation followed by compression. obtain.

2. Osmotic Controlled Release Devices The pharmaceutical compositions provided herein of controlled release dosage forms include osmotic controlled release devices such as, but not limited to, one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT) and extruded cores ( It can be manufactured using an extruding core system (ECS). Generally, such devices have at least two components: (a) a core comprising the active ingredient; and (b) at least one delivery port, with a semipermeable membrane encapsulating the core. The semipermeable membrane controls the influx of moisture from the aqueous use environment to the core such that extrusion causes release of the drug from the delivery port (s).

  In addition to the active ingredient (s), the core of the osmotic device optionally includes an osmotic agent, which is a driving force for the transport of water from the environment of use into the core of the device. To create One type of osmotic agent is a water-swellable hydrophilic polymer, which is also referred to as "osmopolymer" and "hydrogel". Water-swellable hydrophilic polymers suitable as osmotic agents include, but are not limited to, hydrophilic vinyl polymers and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid, poly (methacrylic) acid, polyvinyl pyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer, hydrophobic monomers such as , PVA / PVP copolymers with methyl methacrylate and vinyl acetate, hydrophilic polyurethanes with large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydro Shi cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate and the like.

  Another type of osmotic agent is an osmogen, which can absorb water and provide an osmotic gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, lithium chloride, potassium chloride and sulfate Sodium; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, Sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.

Osmotic agents of various dissolution rates may be used to influence how quickly the active ingredient (s) are initially delivered from the dosage form. For example, amorphous sugars, for example, MANNOGEM ^(TM) EZ, the first few hours immediately to give the desired therapeutic effect resulting in a fast delivery, the remaining amount is gradually continuously discharged desired Can be used to maintain a therapeutic or prophylactic effect at a level of In this case, the active ingredient (s) is released at such a rate as to replace the amount of active ingredient that is metabolized and excreted.

  The core can also include a wide variety of other excipients as described herein to enhance the performance of the dosage form, or to enhance stability or processability.

  Materials useful for the formation of semipermeable membranes include water-permeable and water-insoluble at physiologically relevant pH, or chemical modifications, such as various grades of acrylics, vinyls, ethers that tend to be water insoluble due to crosslinking. , Polyamideamides, polyesters and cellulosics. Examples of suitable polymers useful for forming the coating include plasticized, non-plasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB) , CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p -Toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, -Cast bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acid and ester And poly- (methacrylic) acids and esters and copolymers thereof, starches, dextrans, dextrins, dextrins, chitosans, collagens, gelatins, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes And synthetic waxes.

  The semipermeable membrane may also be a hydrophobic microporous membrane as disclosed in US Pat. No. 5,798,119, in which case the pores are substantially filled with gas, It is not wetted by the aqueous medium but is permeable to water vapor. Such hydrophobic but water vapor permeable membranes are typically hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyhalogens Composed of vinyl chloride, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

  The delivery port (s) on the semipermeable membrane may be formed by mechanical or laser drilling after coating. Also, the delivery port (s) may be formed in situ by erosion of the water soluble substance plug or tearing of the thin portion of the membrane of the well within the core. Delivery ports may also be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in US Pat. Nos. 5,612,059 and 5,698,220.

  The total amount and release rate of the active ingredient (s) released can be substantially controlled by the thickness and porosity of the semipermeable membrane, the composition of the core and the number, size and location of delivery ports.

  The pharmaceutical composition of the osmotic controlled release dosage form may further include conventional additional excipients as described herein for improving the performance or processability of the formulation.

  Osmotic controlled release dosage forms can be prepared according to conventional methods and procedures known to those skilled in the art. Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al., Remington: The Science and Practice of Pharmacy, supra; J. Controlled Release 2002, 79, 7-27.

  In certain embodiments, the pharmaceutical compositions provided herein are formulated as an AMT controlled release dosage form, which comprises the active ingredient (s) and other pharmaceutically acceptable excipients. It comprises an asymmetric osmotic membrane covering a core containing an excipient. See U.S. Patent No. 5,612,059 and International Patent Application Publication No. WO 2002/17918. AMT controlled release dosage forms can be prepared according to conventional methods and procedures known to those skilled in the art, such as direct compression, dry granulation, wet granulation and dip coating methods.

  In certain embodiments, the pharmaceutical compositions provided herein are formulated as an ESC controlled release dosage form, which comprises the active ingredient (s), hydroxyl ethyl cellulose and other pharmaceutically acceptable ones. And a core-coated osmotic membrane comprising an excipient that can be

3. Multi-Particle Controlled Release Device The pharmaceutical composition provided herein of the controlled release dosage form may be fabricated as a multi-particle controlled release device, which has a diameter of about 10 μm to about 3 mm, about 50 μm to about 2.5 mm Or with a large number of particles, granules or pellets ranging from about 100 μm to about 1 mm. Such multi-particles can be made by methods known to those skilled in the art, such as wet and dry granulation, extrusion / granulation, roller compaction, melt congealing, and spray coating of seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre-Selassie Ed .; CRC Press: 2010 and Pharmaceutical Pelletization Technology; Ghebre-Selassie Ed .; CRC Press: 1989.

  Other excipients described herein may be blended with the active ingredient (s) to aid in multi-particle processing and formation. The resulting particles may themselves constitute the multiparticle device and may be coated with various film forming materials, such as enteric polymers, water-swellable and water-soluble polymers. The multiparticles may be further processed as capsules or tablets.

4. Targeted Delivery Also, for example, liposome-based delivery systems, releasing red blood cells, such that the pharmaceutical compositions provided herein are targeted to specific tissues, receptors or other body areas of the subject to be treated. It may be formulated into a base delivery system, and an antibody based delivery system. Examples include, but are not limited to, US Pat. Nos. 5,709,874; 5,759,542; 5,840,674; 5,900,252; No. 366; No. 5, 985, 307; No. 6, 004, 534; No. 6, 039, 975; No. 6, 048, 736; Nos. 6,071,495; 6,120,751; 6,131,570; 6,139,865; 6,253,872; 6,271, Nos. 359; 6,274,552; 6,316,652; and 7,169,410.

Methods of Use The compounds provided herein have activity as inhibitors of Janus kinase and are thus useful for the treatment of diseases associated with Janus kinase activity. By inhibiting Janus kinase, the compounds provided herein inhibit or modulate signal transduction and transcription activation factor (STAT) protein phosphorylation, thereby causing transcription of genes leading to altered cellular function. Useful for blocking or regulating.

  Thus, in one embodiment, the provided compounds are provided to mammals (eg, humans) for the treatment of various conditions and disorders, including but not limited to cartilage destruction, degeneration of bones and / or joints, and the like. And related conditions such as osteoarthritis; and / or conditions involving inflammation or an immune response such as Crohn's disease, rheumatoid arthritis, asthma, rhinitis, psoriasis, juvenile idiopathic arthritis, colitis, inflammatory Enteric diseases, lupus, endotoxin-driven disease states (eg, complications after bypass surgery or chronic endotoxin state contributing eg to chronic heart failure); diseases with impaired cartilage metabolism, eg, congenital malformations of cartilage Administered to treat, prevent or delay the progression of diseases associated with hypersecretion of IL6 as well as transplant rejection, eg organ transplant rejection. Inhibitors of Janus kinase are also useful in the treatment of proliferative diseases such as leukemia and solid tumors.

  In another embodiment, a compound provided herein to a subject herein, such as a compound of any one of Formulas (A)-(I) or one of its enantiomers, racemic mixture, diastereomers Mer mixture or isotopic variant; or one or more symptoms of a Janus kinase mediated condition, disorder or disease of a subject comprising administering a pharmaceutically acceptable salt, solvate or prodrug thereof Provide methods for treatment, prevention or amelioration.

  In certain embodiments, the Janus kinase mediated condition, disorder or disease is a proliferative disorder. In certain embodiments, the Janus kinase mediated condition, disorder or disease is an inflammatory disease. In certain embodiments, the Janus kinase mediated condition, disorder or disease is a cardiovascular disease. In certain embodiments, the Janus kinase mediated condition, disorder or disease is an immune disorder. In certain embodiments, the Janus kinase mediated condition, disorder or disease is cancer. In certain embodiments, the Janus kinase mediated condition, disorder or disease is osteoarthritis, Crohn's disease, rheumatoid arthritis, asthma, rhinitis, psoriasis, juvenile idiopathic arthritis, ulcerative colitis, inflammatory Intestinal disease, epilepsy, chronic heart failure, birth defects in cartilage, alopecia, dry eye, transplant rejection, leukemia or solid tumor.

  In certain embodiments, the Janus kinase mediated condition, disorder or disease is a JAK1 mediated condition, disorder or disease. In certain embodiments, the JAK1-mediated condition, disorder or disease is a proliferative disease. In certain embodiments, the JAK1-mediated condition, disorder or disease is an inflammatory disease. In certain embodiments, the JAK1-mediated condition, disorder or disease is a cardiovascular disease. In certain embodiments, the JAK1-mediated condition, disorder or disease is an immune disorder. In certain embodiments, the JAK1-mediated condition, disorder or disease is cancer.

  In certain embodiments, the Janus kinase mediated condition, disorder or disease is a JAK2 mediated condition, disorder or disease. In certain embodiments, the JAK2-mediated condition, disorder or disease is a proliferative disorder. In certain embodiments, the JAK2-mediated condition, disorder or disease is an inflammatory disease. In certain embodiments, the JAK2-mediated condition, disorder or disease is a cardiovascular disease. In certain embodiments, the JAK2-mediated condition, disorder or disease is an immune disorder. In certain embodiments, the JAK2-mediated condition, disorder or disease is cancer.

  In certain embodiments, the Janus kinase mediated condition, disorder or disease is a JAK3 mediated condition, disorder or disease. In certain embodiments, the JAK 3-mediated condition, disorder or disease is a proliferative disorder. In certain embodiments, the JAK 3-mediated condition, disorder or disease is an inflammatory disease. In certain embodiments, the JAK 3-mediated condition, disorder or disease is a cardiovascular disease. In certain embodiments, the JAK 3-mediated condition, disorder or disease is an immune disorder. In certain embodiments, the JAK 3-mediated condition, disorder or disease is cancer.

  In certain embodiments, the Janus kinase-mediated condition, disorder or disease is a TYK2-mediated condition, disorder or disease. In certain embodiments, the TYK2-mediated condition, disorder or disease is a proliferative disorder. In certain embodiments, the TYK2-mediated medical condition, disorder or disease is an inflammatory disease. In certain embodiments, the TYK2-mediated medical condition, disorder or disease is a cardiovascular disease. In certain embodiments, the TYK2-mediated condition, disorder or disease is an immune disorder. In certain embodiments, the TYK2-mediated condition, disorder or disease is cancer.

  In yet another embodiment, a compound provided herein to a subject, such as a compound of any one of Formulas (A)-(I) or one of its enantiomers, racemic mixture, dia Treating, preventing or ameliorating one or more symptoms of a proliferative disorder in a subject comprising administering a stereomeric mixture or isotopic variant; or a pharmaceutically acceptable salt, solvate or prodrug thereof Provide a way to

  In certain embodiments, the proliferative disorder is an inflammatory disorder. In certain embodiments, the proliferative disorder is an immune disorder.

  In certain embodiments, the proliferative disorder is allergy, alopecia, amyotrophic lateral sclerosis, ankylosing spondylitis, arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, asthma, atopic dermatitis, Behcet Disease, colitis, chronic obstructive pulmonary disease, Crohn's disease, dry eye, inflammatory bowel disease, leukemia, lymphoma, myelofibrosis, multiple sclerosis, osteoarthritis, polycythemia, psoriasis, rhinitis, dryness syndrome Solid tumor, systemic lupus erythematosus, transplant rejection or ulcerative colitis. In certain embodiments, the proliferative disorder is inflammatory bowel disease, psoriasis, rheumatoid arthritis, organ graft rejection. In certain embodiments, the proliferative disorder is ankylosing spondylitis, asthma, Behcet's disease, celiac disease, inflammatory bowel disease, psoriasis, primary biliary cirrhosis, rheumatoid arthritis, Sjögren's syndrome or systemic lupus erythematosus. . In certain embodiments, the proliferative disorder is alopecia areata, atopic dermatitis, inflammatory bowel disease, organ graft rejection, psoriasis, rheumatoid arthritis, ulcerative colitis or vitiligo. In certain embodiments, the proliferative disorder is a myeloproliferative disorder. In certain embodiments, the proliferative disorder is lymphoma, myelofibrosis, pancreatic cancer or erythrocytosis.

  In certain embodiments, the proliferative disorder is cancer. In certain embodiments, the cancer is a recurrent cancer. In certain embodiments, the cancer is a drug resistant cancer. In certain embodiments, the cancer is a drug resistant recurrent cancer. In certain embodiments, the cancer is a multidrug resistant cancer. In certain embodiments, the cancer is a multidrug resistant recurrent cancer.

  In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human primate, a domestic animal such as a cattle, a sport animal or a companion animal such as a horse, a dog or a cat.

  In certain embodiments, conditions, disorders or diseases treatable with the compounds provided herein include, but are not limited to: (1) inflammatory or allergic diseases such as systemic anaphylaxis and hypersensitivity Disorders, atopic dermatitis, urticaria, drug allergy, insect bite allergy, food allergy (eg, celiac disease) and mastocytosis; (2) inflammatory bowel disease such as Crohn's disease, ulcerative colitis, (3) Vasculitis and Behcet's syndrome; (4) Psoriasis and inflammatory skin diseases such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral skin disease (Eg, human papilloma virus, derived from HIV or RLV infection), skin by bacteria, fungi and other parasites Disease and skin lupus erythematosus; (5) asthma and respiratory allergic diseases such as allergic asthma, exercise-induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity lung disease and chronic obstructive pulmonary disease; 6) Autoimmune diseases such as arthritis (eg rheumatic and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease and glomerulonephritis; (7) transplant rejection (7) For example, allotransplant rejection and graft versus host disease), eg skin graft rejection, solid organ graft rejection, bone marrow transplantation rejection; (8) fever; (9) cardiovascular disorders such as acute heart failure, low blood pressure, high blood pressure Angina, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis and angiostenosis; (10) cerebrovascular disorder, eg Traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm; (11) breast, skin, prostate, cervix, uterus, ovary, testis, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (eg , Esophagus, stomach, pancreas), brain, thyroid, cancer of the blood and lymph system; (12) fibrosis, connective tissue disease and sarcoidosis, (13) genital and genital condition such as erectile dysfunction; (14) gastrointestinal Vascular disorders such as gastritis, ulcers, nausea, pancreatitis and vomiting; (15) neurological disorders such as Alzheimer's disease; (16) sleep disorders such as insomnia, narcolepsy, sleep apnea syndrome and Pickwick syndrome (17) pain; (18) nephropathy; (19) ocular disorders such as glaucoma; and (20) infectious diseases such as HIV.

  In certain embodiments, proliferative diseases treatable with compounds provided herein include, but are not limited to: (1) leukemia, such as, but not limited to, acute leukemia, acute lymphocytic leukemia, acute bone marrow Leukemia, such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, leukemia and myelodysplastic syndrome or symptoms thereof (eg, anemia, thrombocytopenia, neutropenia Pycosis or pancytopenia), refractory anemia (RA), RA with cyclic iron blasts (RARS), RA with excess blasts (RAEB), transitional RAEB (RAEB-T), Leukemia and chronic myelomonocytic leukemia (CMML), (2) chronic leukemia such as, but not limited to, chronic myelogenous (granulocytic) leukemia, chronic lymphocytic leukemia and hairy cell leukemia; (3) true (4) lymphomas, such as, but not limited to, Hodgkin's disease and non-Hodgkin's disease; (5) multiple myeloma, such as, but not limited to, smoldering multiple myeloma, non-secretory myeloma, osteosclerotic Myeloma, plasma cell leukemia, sporadic plasmacytoma and extramedullary plasmacytoma; (6) wardenstream macroglobulinemia; (7) monoclonal gammaglobulinemia of unknown significance (8 )) Benign monoclonal gamma globulinemia; (9) heavy chain disease; (10) sarcomas of bone and connective tissue, such as, but not limited to, bone sarcomas, osteosarcomas, chondrosarcomas, Ewing sarcomas, giant cell carcinoma of the malignancy, Fibrosarcoma of bone, chordoma, periosteal sarcoma, soft tissue sarcoma, hemangiosarcoma (angiosarcoma (hemangiosarcoma)), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphatic sarcoma, metastatic cancer, schwannoma, side (11) Brain tumors, such as, but not limited to, gliomas, astrocytomas, brain stem gliomas, epithelioma, oligodendrogliomas, non-gliocytic tumors, auditory neurialomas, Craniopharyngiomas, medulloblastomas, meningiomas, pineal somatomas, pineoblastomas and primary brain lymphomas; (12) breast cancer such as, but not limited to, adenocarcinoma, lobular (small cell) cancer Intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular mammary carcinoma, papillary breast cancer, primary cancer, Paget's disease and inflammatory breast cancer; (13) cancer of the adrenal gland, such as, but not limited to, chromaffin cells Tumor and adrenocortical carcinoma; (14) thyroid cancer such as, but not limited to, papillary or follicular thyroid cancer, medullary thyroid carcinoma and anaplastic thyroid cancer; (15) pancreatic cancer such as, but not limited to But there are insulinomas, gastrinomas, Gonomas, biplomas, somatostatin secreting tumors and carcinoid tumors or islet cell tumors; (16) Pituitary cancer, such as, but not limited to, Cushing's disease, prolactin secreting tumors, acromegaly and diabetes insipius; (17) Eye cancers such as, but not limited to intraocular melanoma such as iris melanoma, choroidal melanoma and ciliary melanoma and retinoblastoma; (18) vaginal cancer such as, but not limited to squamous epithelium Cancer, adenocarcinoma and melanoma; (19) vulvar cancer such as, but not limited to squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma and Paget's disease; (20) cervical cancer such as, but not limited to Squamous cell carcinoma and adenocarcinoma; (21) uterine cancer such as, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer such as, but not limited to, on the ovaries Skin cancer, borderline tumor, germ cell tumor and interstitial tumor; (23) esophagus cancer such as, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucinous epidermoid carcinoma, adenosquamous cell carcinoma, sarcoma , Melanoma, plasmacytoma, squamous cell carcinoma and oat cell (small cell) carcinoma; (24) gastric cancer, for example, but not limited to, adenocarcinoma, mycelial growth (polypoid), ulcerative, superficial enlargement , Diffuse spread, malignant lymphoma, liposarcoma, fibrosarcoma and carcinosarcoma; (25) colon cancer; (26) rectum cancer; (27) liver cancer such as, but not limited to, hepatocellular carcinoma and hepatoblastoma (28) gallbladder cancer such as, but not limited to, adenocarcinoma; (29) cholangiocarcinoma such as, but not limited to, papillary, nodular and diffuse; (30) lung cancer such as, but not limited to, non-small cell lung cancer , Squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma and small Alveolar lung cancer; (31) testicular cancer such as, but not limited to, germ cell tumor, seminoma, anaplastic, classical (typical), spermatogenic, non-seminoma, embryonal carcinoma, teratoma cancer and villous Cancer (yolk sac tumor); (32) prostate cancer such as, but not limited to, adenocarcinoma, leiomyosarcoma and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, such as limited But not squamous cell carcinoma; (35) base cancer; (36) salivary gland cancer, such as, but not limited to, adenocarcinoma, mucinous epidermoid carcinoma and adenoid cystic carcinoma; (37) pharyngeal cancer, such as, but not limited to (38) skin cancer such as, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spread melanoma, nodular melanoma, malignant melanoma melanoma And terminal lentigo melanoma; (39) kidney cancer, eg Without limitation, renal cell carcinoma, adenocarcinoma, adrenal carcinoma, fibrosarcoma and transitional cell carcinoma (renal pelvis and / or ureteral carcinoma); (40) Wilms tumor; (41) bladder cancer such as, but not limited to, metastasis Epithelial cancer, squamous cell carcinoma, adenocarcinoma and carcinosarcoma; and (42) other cancers such as, but not limited to, myxosarcoma, osteogenic sarcoma, endothelial sarcoma, lymphatic-endothelial sarcoma, mesothelioma, There may be mentioned liquid membrane tumor, hemangioblastoma, epithelial cancer, cyst adenocarcinoma, bronchogenic carcinoma, sweat adenocarcinoma, sebaceous adenocarcinoma, papillary carcinoma and papillary adenocarcinoma. See, eg, Fishman et al., Medicine, 2d ed., JB Lippincott Co., Philadelphia: 1985; and Murphy et al., Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin: 1997. Of.

  Depending on the disorder, disease or condition to be treated and the condition of the subject, the compounds or pharmaceutical compositions provided herein may be oral, parenteral (eg intramuscular, intraperitoneal, intravenous, ICV, cisterna Internal injection or infusion, subcutaneous injection or implantation), by inhalation, nasally, vaginally, rectally, sublingually or by transsurface (e.g. transdermal or topical) administration route, alone or in a suitable dosage unit They may be formulated together with pharmaceutically acceptable excipients suitable for each route of administration. Also provided herein is the administration of a compound or pharmaceutical composition provided herein in a depot preparation which releases the active ingredient over a predetermined period of time.

  In the treatment, prevention or amelioration of one or more symptoms of a disorder, disease or condition described herein, a suitable dosage level generally will be about 0.001 to about 100 mg / kg subject body weight / day ( mg / kg / day), about 0.01 to about 75 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.5 to about 25 mg / kg / day or about 1 to about 20 mg / kg / Day, which can be administered in single or multiple doses. Within this range, the dosage is from about 0.005 to about 0.05, about 0.05 to about 0.5, about 0.5 to about 5.0, about 1 to about 15, about 1 to about 20 or It may range from about 1 to about 50 mg / kg / day.

  For oral administration, the pharmaceutical compositions provided herein are tablets, each containing about 1.0 to about 1,000 mg of the active ingredient, and in one embodiment, to the subject to be treated. About 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, for dose adjustment. It can be formulated in the form of tablets containing about 500, about 600, about 750, about 800, about 900 and about 1,000 mg of the active ingredient. The pharmaceutical compositions provided herein may be administered on a regimen of 1 to 4 times per day, such as once, twice, three times and four times per day.

  However, the specific dose level and dosing frequency for any specific subject may vary, and various factors such as activity of the specific compound used, metabolic stability of the compound and length of action It will be appreciated that it depends on the subject being treated, age, weight, general health, sex, diet, mode and duration of administration, excretion rate, drug combination, severity of the particular condition and the subject being treated. .

  In one embodiment, herein a method for modulating the activity of a tyrosine kinase, in one embodiment a Janus kinase, a compound provided herein, such as, for example, Formula (A) A method comprising contacting with any one compound of I) or one of its enantiomers, racemic mixture, diastereomeric mixture or isotopic variant; or a pharmaceutically acceptable salt, solvate or prodrug thereof I will provide a.

  In another embodiment, a compound disclosed herein in the subject, eg, a compound of any one of Formulas (A)-(I) or one of its enantiomers, racemic mixture, diastereomers A method for modulating activity of a tyrosine kinase, in one embodiment a Janus kinase, in a subject, comprising administering a mer mixture or isotopic variant; or a pharmaceutically acceptable salt, solvate or prodrug thereof I will provide a.

  In certain embodiments, the Janus kinase is JAK1. In certain embodiments, the Janus kinase is JAK2. In certain embodiments, the Janus kinase is JAK3. In certain embodiments, the Janus kinase is TYK2.

  In certain embodiments, the compounds provided herein are selective inhibitors of JAK1. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold with respect to JAK1 over JAK2 It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over JAK1 over JAK3. It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over JAK1 over TYK2 It has selectivity in the range of 200 times, about 500 times or about 1000 times.

  In certain embodiments, the compounds provided herein are selective inhibitors of JAK2. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over JAK2 over JAK1. It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold with respect to JAK2 over JAK3. It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over JAK2 over TYK2. It has selectivity in the range of 200 times, about 500 times or about 1000 times.

  In certain embodiments, the compounds provided herein are selective inhibitors of JAK3. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over JAK3 over JAK1. It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold with respect to JAK3 over JAK2 It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over JAK3 over TYK2. It has selectivity in the range of 200 times, about 500 times or about 1000 times.

  In certain embodiments, the compounds provided herein are selective inhibitors of TYK2. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over TYK2 over JAK1. It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over TYK2 over JAK3. It has selectivity in the range of 200 times, about 500 times or about 1000 times. In certain embodiments, the compounds provided herein are about 2-fold, about 4-fold, about 8-fold, about 20-fold, about 50-fold, about 100-fold, about 100-fold, about 2-fold over TYK2 over JAK3. It has selectivity in the range of 200 times, about 500 times or about 1000 times.

In certain embodiments, the selectivity of the compounds provided herein for the first kinase over the second kinase is determined by the first kinase for the IC ₅₀ value for the second kinase of the compound. It is determined by the ratio of IC ₅₀ values.

  The present disclosure includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one compound provided herein alone or in combination with a pharmaceutical carrier or diluent. Optionally, the compounds provided herein alone, in combination with other compounds provided herein, or one or more other therapeutic agents (one or more) having similar therapeutic activity Or other pharmaceutically active substances, such as anti-inflammatory agents or other pharmaceutically active substances.

  Thus, a compound provided herein, such as a compound of any one of formulas (A) to (I) or its enantiomers, enantiomeric mixtures, mixtures of two or more diastereomers or isotopic variants; or a medicament thereof Are also useful for the treatment, prevention or amelioration of one or more symptoms of a condition, disorder or disease in which the compounds provided herein are useful. Can be combined or combined with other agents or treatments.

  Also, other suitable therapeutic agents include, but are not limited to: (1) an alpha adrenergic agent; (2) an antiarrhythmic agent; (3) an antiatherogenic agent such as an ACAT inhibitor; (4) an antibiotic Eg, anthracyclines, bleomycins, mitomycins, dactinomycins and plicamycins; (5) anticancer and cytotoxic agents such as alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethyleneimines And triazene; (6) anticoagulants such as acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin and ximelagatran; (7) antidiabetic agents such as biguanides such as metformin , Glucosidase inhibition (Eg, acarbose), insulin, meglitinide (eg, repaglinide), sulfonylureas (eg, glimepiride, glyburide and glipizide), thiozolidinediones (eg, troglitazone, rosiglitazone and pioglitazone) and PPAR-γ agonists; ) Antifungal agents, for example, amorolfine, amphotericin B, anidurafungin, bifonazole, butenafine, butoconazole, butpoconazole, caspofungin, ciclopirox, clotrimazole, econazole, phenniconazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin , Miconazole, naftifine, natamycin, nystatin, oxiconazole, labconazole, posaconazole, li Sidine, sertaconazole, sulconazole, terbinafine, terconazole, thioconazole and voriconazole; (9) anti-inflammatory agents such as non-steroidal anti-inflammatory agents such as aceclofenac, acemetacin, amoxiprine, aspirin, azapropazone, benolate, bromfenac , Carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine (faislamine), fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, Meclofenamic acid, mefenamic acid, meloxicam, metamizole, salicylic acid (G) magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, thiaprofenic acid and tolmetin; (10) antimetabolites For example, antifolates, purine analogs and pyrimidine analogs; (11) antiplatelet agents such as GPIIb / IIIa blockers (eg abciximab, eptifibatide and tirofiban), P2Y (AC) antagonists (eg clopidogrel, ticlopidine and CS- 747), cilostazol, dipyridamole and aspirin; (12) antiproliferative agents such as methotrexate, FK 506 (tacrolimus) and mycofenor Acid mofetil; (13) anti-TNF antibodies or soluble TNF receptors such as etanercept, rapamycin and leflunimide; (14) aP2 inhibitors; (15) β-adrenergic agonists such as carvedilol and metoprolol; ) Bile acid separating agents such as questran; (17) calcium channel blockers such as amlodipine besylate; (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors such as (20) cyclosporin; (21) cytotoxic agents such as azathioprine and cyclophosphamide; (22) diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethic; Azide, methyl chlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrylic acid, ticrynaphen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride and spironolactone; (23) endothelin converting enzyme (ECE) inhibitors such as phosphoramidon; (24) Enzymes, such as L-asparaginase; (25) Factor VIIa inhibitors and Factor Xa inhibitors; (26) Farnesyl-protein transferase inhibitors; (27) Fibrates; (28) Growth factor inhibitors, such as (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, K-104 (also known as itavastatin, nisvastatin ("nisvastatin" or "nisbastatin") and ZD-4522 (also known as rosuvastatin, atavastatin or visastatin); neutral endopeptidase (NEP) inhibitors; 31) Hormonal agents such as glucocorticoids (eg cortisone), estrogens / antiestrogens, androgens / antiandrogens, progestins and luteinizing hormone releasing hormone antagonists and octreotide acetate; (32) immunosuppressants; (33) Mineralo Corticoid receptor antagonists such as spironolactone and eplerenone; (34) microtubule disrupting agents such as ectenasisin; (35) microtubule stabilizing agents such as paclitaxel (pacitaxel), docetaxel and epo (36) MTP inhibitors; (37) niacin; (38) phosphodiesterase inhibitors such as, for example, PDE III inhibitors (eg cilostazol) and PDE V inhibitors (eg sildenafil, tadalafil and vardenafil); (39) plant-derived preparations such as vinca alkaloids, epipodophyllotoxins and taxanes; (40) platelet activating factor (PAF) antagonists; (41) platinum coordination complexes such as cisplatin, satraplatin and carboplatin; (42) potassium channel openers; (43) prenyl-protein transferase inhibitors; (44) protein tyrosine kinase inhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors; (47) steroids, for example, Aldosterone Beclomethasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone and triamcinolone; (48) TNF-α inhibitors such as tenidap (tenidap); (49) Thrombin inhibitors such as hirudin; (50) thrombolytic agents such as anistreplase, reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoyl group plasminogen strept Kinase activator complex (APSAC); (51) thromboxane receptor antagonist, such as ifetroban; (52) topoisomerase inhibitor (53) Vasopeptidase inhibitors (NEP-ACE dual inhibitors) such as omapatrilate and gemopatrilate; and (54) other miscellaneous agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine and gold compounds May be mentioned.

  In certain embodiments, other treatments that may be used in conjunction with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biological response modifiers (eg, interferons, etc.) Interleukin and tumor necrosis factor (TNF), hyperthermia and cryotherapy and agents to attenuate adverse effects such as antiemetics (antiemetics).

  The compounds provided herein may be used with other Janus kinase inhibitors or one or more other suitable therapeutic agents useful for the treatment of the aforementioned disorders, such as: anti-inflammatory, anti-arthritic, anti-autoimmune Anti-graft rejection agent, anti-asthmatic agent, anti-rhinitis agent, anti-chronic obstructive pulmonary disease (COPD) agent, anti-inflammatory enteric agent, anti-systemic lupus erythematosus agent, anti-psoriatic agent and / or anti-proliferative agent You may use it.

  Examples of suitable anti-inflammatory agents for use in combination with the compounds provided herein include, but are not limited to, azathioprine, corticosteroids (eg, prednisolone and dexamethasone), cyclophosphamide, cyclosporin A, Tacrolimus, mycophenolate mofetil, muromonab-CD3, ATG, aspirin, acetaminophen, ibuprofen, naproxen, celebrex and piroxicam.

  Examples of suitable anti-arthritic agents for use in combination with the compounds provided herein include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMWARDS (methotrexate, leflunomide, sulfasalazine, These include auranohum (auranofm), sodium gold thiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine and cyclosporin) and biological DMWARDS (infliximab, etanercept, adalimumab, rituximab and abatacept).

Examples of suitable anti-autoimmune agents for use in combination with the compounds provided herein include, but are not limited to, glucocorticoids, cytostatic agents (purine analogs), alkylating agents (cyclophosphamide) (Nitrosoureas and platinum compounds), anti-metabolites (methotrexate, azathioprine and mercapulopurine), cytotoxic antibiotics (dactinomycin anthracycline, mitomycin C, blemocyin and mithramycin), antibodies (anti-CD20, anti CD-25, anti-CD3 (OTK3), monoclonal antibodies, ATGAM ^(R) and thymoglobulin), cyclosporine, tacrolimus, rapamycin (sirolimus (Siolimus)), interferons (e.g., IFN-beta), TNF binding protein (Infliximab (Infiximab)), etanercept and adalimumab), mycophenolate, Fingolimod or myriocin (Samojimoshijin (Thermozymocidin)) can be mentioned.

  Examples of suitable anti-transplant rejection agents for use in combination with the compounds provided herein include, but are not limited to, calcineurin inhibitors (eg, cyclosporin and tacrolimus (FK506)), mTOR inhibitors (eg, Sirolimus and everolimus), antiproliferative agents (eg azathioprine and mycophenolic acid), corticosteroids (eg prednisolone and hydrocortisone), antibodies (eg monoclonal anti-IL-2Rα receptor antibodies, basiliximab and daclizumab), polyclonal anti-T Cellular antibodies such as anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) are included.

  Examples of suitable anti-asthmatic and / or anti-nasinitis and / or anti-COPD agents for use in combination with the compounds provided herein include, but are not limited to, beta 2-adrenergic receptor agonists (e.g. Salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhalation type or tablet), anticholinergic (eg ipratropium bromide), glucocorticoid (oral or inhalation type), long-acting β2-agonist ( For example, salmeterol, formoterol, bambuterol and sustained-release oral albuterol), a combination of inhaled steroid and long-acting bronchodilator (eg, fluticasone / salmeterol and budesonide / formoterol), leukotriene antagonists and synthetic inhibitors (eg, molycotriene) Interlukast, zafirlukast and zileuton), inhibitors of mediator release (eg cromoglycate and ketotifen), biological modulators of IgE response (eg omalizumab), antihistamines (eg ceteridin, cinnarizine and fexofenadine) And vasoconstrictors such as oxymetazoline, xylometazoline, naphazoline and tramazoline. The compounds provided herein may also be administered in combination with emergency medications for asthma and / or COPD, such therapeutic agents include administration of oxygen or heliox, salbutamol or terbutaline with a nebulizer (Optionally, in combination with anticholinergics (eg ipratropium)) systemic steroids (orally or intravenously, eg prednisone, prednisolone, methylprednisolone, dexamethasone and hydrocortisone), intravenous salbutamol, non-specific beta -Agonists (injection or inhalation) (e.g. epinephrine, isoetharine, isoproterenol and metaproterenol), anticholinergics (e.g. with glycopyrrolate, atropine and ipratropium with IV or nebuliser) Nchin (e.g., theophylline, aminophylline and bamifylline), inhalation anesthetics have bronchodilator effects (e.g., isoflurane, halothane and enflurane) include ketamine or intravenous magnesium sulfate.

  Suitable anti-inflammatory enteric agents for use in combination with the compounds provided herein include, but are not limited to: glucocorticoids (eg, prednisone and budesonide), synthetic disease modifying immunomodulators (eg, Included are methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaploprine and cyclosporine) and biological disease modifying immunomodulators (eg, infliximab, adalimumab, rituximab and abatacept).

  Examples of suitable anti-systemic lupus erythematosus agents for use in combination with the compounds provided herein include, but are not limited to, disease-modifying anti-rheumatic drugs (DMARDs), such as anti-malarial drugs (eg, plakenyl and Hydroxychloroquine), immunosuppressants (eg methotrexate and azathioprine), cyclophosphamide, mycophenolic acid, immunosuppressants and analgesics, eg non-steroidal anti-inflammatory drugs, opiates (eg dextropropoxyphen and Included are cocodamol), opioids (e.g. hydrocodone, oxycodone, MS contin and methadone) and fentanyl duragesic transdermal patches.

Examples of suitable anti-psoriatic agents for use in combination with the compounds provided herein include, but are not limited to, trans-surface treatments such as bath solutions, moisturizers, medicinal creams, and coles Tar-containing ointment, dithranol (anthralin), corticosteroids such as desoxymethasone ⁽ eg TOPICORT®), fluocinonide, vitamin D3 analogues (eg calcipotriol), argan oils and retinoids (eg etretinate) , Acitretin and tazarotene), systemic treatment agents such as methotrexate, cyclosporine, retinoid, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid ester or organisms Agents, for example, alefacept, etanercept, adalimumab, infliximab, include efalizumab and Usutekinumabu (IL-12 and IL-23 blocking agent). The compounds provided herein may also be administered in combination with other treatments, such as, but not limited to, phototherapy or photochemotherapy (eg, psoralen and ultraviolet A-wave phototherapy (PUVA)).

  Examples of suitable antiproliferative agents for use in combination with the compounds provided herein include, but are not limited to, methotrexate, leucovorin, adriamycin, prenisone, bleomycin, cyclophosphamide, 5-fluorouracil , Paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megesterol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (eg trastuzumab), capecitabine, raloxifene hydrochloride, EGFR inhibitor (eg gefitinib , Erlotinib, cetuximab), VEGF inhibitors (eg, bevacizumab), proteasome inhibitors (eg, bortezomib), imatinib or sp90 inhibitors (e.g., 17-AAG) and the like. The compounds provided herein may also be administered in combination with other treatments, such as, but not limited to, radiation therapy or surgery. In a specific embodiment, the proliferative disorder is cancer, myeloproliferative disease or leukemia.

  Such other agents or drugs are compounds generally provided herein, such as compounds of any one of Formulas (A)-(I) or enantiomers thereof, in the routes and amounts generally used for them. Or a mixture of two or more diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, simultaneously or sequentially. When the compounds provided herein are used in combination with one or more other drugs, pharmaceutical compositions containing such other drugs may be used in addition to the compounds provided herein. , Not required. Thus, the pharmaceutical compositions provided herein also include those that also contain one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

  The weight ratio of the compound provided herein to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, each of the effective doses is used. Thus, for example, when the compounds provided herein are used in combination with an NSAID, the weight ratio of said compound to the NSAID is about 1,000: 1 to about 1: 1,000 or about 200: 1 to about 1: 200 It may be a range. Also, while the sum of the compounds provided herein and the other active ingredients is generally within the stated ranges, in each case an effective dose of each active ingredient may be used.

  The compounds provided herein may also be provided as articles of manufacture using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes and any suitable for the selected formulation and intended mode of administration and treatment. Packaging material is mentioned.

  In certain embodiments, provided herein are kits that can simplify the administration of appropriate amounts of the active ingredient to a subject when used by a physician. In certain embodiments, the kits provided herein comprise a container and a compound provided herein, eg, a compound of any one of Formulas (A)-(I) or an enantiomer, enantiomer thereof A mixture, a mixture of two or more diastereomers or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug dosage form thereof.

  In certain embodiments, the kit comprises a compound provided herein, eg, a compound of any one of Formulas (A)-(I) or an enantiomer, a mixture of enantiomers, two or more diastereomers thereof Or a container provided with a dosage form of a mixture or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, as described herein in a container. It has more than one type of other therapeutic agent.

  The kits provided herein may further include a device used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringes, infusion bags, patches and inhalers. The kits provided herein may also include a contraceptive for the administration of the active ingredient.

  The kits provided herein may further comprise a pharmaceutically acceptable vehicle that may be used to administer one or more active ingredients. For example, if the active ingredient is provided in solid form which must be reconstituted for parenteral administration, the kit dissolves the active ingredient to form a sterile solution suitable for parenteral administration without microparticles. It may be provided with a suitable vehicle sealed container to obtain. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles such as, but not limited to, water for injection USP, sodium chloride injection, Ringer's injection, dextrose injection, dextrose / sodium chloride injection and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate And benzyl benzoate.

  The present disclosure will be further understood by the following non-limiting examples.

As used herein, the symbols and notations used in these methods, schemes and examples refer to the most up-to-date scientific literature, eg, Journal, regardless of whether a particular abbreviation is specifically defined. It conforms to that used in the American Chemical Society or the Journal of Biological Chemistry. Specifically, without limitation, the following abbreviations may be used in the Examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); L (liter); mM (mmole concentration); μM (micro molar concentration); Hz (hertz); MHz (megahertz); J (coupling constant); mmol (mmole); (Equivalents); ppm (parts per million); h, hr or hrs (hours); min (minutes); RT or rt (room temperature); sat. Or sat'd (saturated); aq. (Aqueous); MS (mass spectrometric analysis); NMR (nuclear magnetic resonance); HPLC (high performance liquid chromatography or high pressure liquid chromatography); LC / MS (high performance liquid chromatography / mass spectrometric analysis); TLC (thin layer chromatography) ACN or MeCN (acetonitrile); AcOH or HOAc (acetic acid); CDCl ₃ (deuterated chloroform); DCM (dichloromethane); DMF (N, N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d ₆ ( deuterated dimethyl sulfoxide); EtOAc or EA (ethyl acetate); _Et 2 O (diethyl ether); EtOH (ethanol); MeOH (methanol); t-BuOH (tert- butanol); PE (petroleum ether); THF ( Tetrahydrofuran ); DIPEA (N, N-diisopropylethylamine); TEA or _Et 3 N (tri ethylamine); TFA (trifluoroacetic _{acid); Pd (dppf) Cl 2} ([1,1'- bis (diphenylphosphino) ferrocene] Dichloropalladium); B ₂ (pin) ₂ (bis (pinacolato) diboron); DPPA (diphenylphosphoryl azide); Me (methyl); Et (ethyl); iPr, (isopropyl); tBu (tert-butyl); tert-Butoxycarbonyl (carbonyl)); Bn (benzyl); Ph (phenyl); and AcO (acetate).

  Standard processing and purification methods known to those skilled in the art can be used for all the following examples. All temperatures are given in units of ° C. (degrees Celsius) unless otherwise stated. All reactions were performed at room temperature unless otherwise stated. The synthetic methodology herein is intended to illustrate applicable chemistry by the use of specific examples and is not intended to indicate the scope of the present disclosure.

Example A
In Vitro Assay for Measurement of Inhibition of Janus Kinase In vitro inhibition of recombinant human JAK was measured as follows.

Compounds were tested in LanthaScreen ^(TM) time-resolved fluorescence resonance energy transfer (TR-FRET) enzyme assay (manufactured by Invitrogen). The human Janus kinase 1 (JAK1) used in the assay is a recombinant JAK1 catalytic domain (amino acids 866-1154) (Invitrogen, Catalog No. PV4774) expressed and purified in insect cells. The human Janus kinase 2 (JAK2) used in the assay is a recombinant JAK2 catalytic domain (amino acids 808-1132) (Invitrogen, catalog number PV4210) expressed and purified in insect cells. The human Janus kinase 3 (JAK3) used in the assay is a recombinant JAK3 catalytic domain (amino acids 781 to 1124) (Invitrogen, Catalog No. PV3855) expressed and purified in insect cells. The human tyrosine kinase 2 (TYK2) used in the assay is a recombinant TYK2 catalytic domain (amino acids 833-1187) (Invitrogen, Catalog No. PV 4790) expressed and purified in insect cells. The substrate is recombinant STAT1 (Invitrogen, Catalog No. PV5211) expressed as a fusion with GFP (green fluorescent protein) to act as a physiological substrate.

Test compounds were prepared and diluted in DMSO to make 3-fold serial dilutions of 10 step doses up to 100 × of the final test concentration. The compounds were then further diluted to 4 × with kinase reaction buffer (Invitrogen, catalog number PV3189). Testing of the compound's enzyme reaction was performed in a white 384-well polypropylene plate (Packard, catalog number 6005214), 440 ng / mL JAK1, 11 ng / mL JAK2, 400 ng / mL JAK3 or 200 ng / mL TYK2, 100 nM substrate and Performed in a total reaction volume of 10 μL containing 1 mM ATP. The assay is initiated by loading 2.5 μL of JAK1, JAK2, JAK3 or TYK2 (diluted in kinase reaction buffer) into wells followed by an equal volume of 4 for a 15 minute incubation at room temperature for pretreatment. X Compound was added. The enzymatic reaction was initiated by the addition of a mixture of 5 μL of substrate and ATP (prepared in kinase reaction buffer). After 1 hour reaction, a mixture of 10 μL of EDTA (final 10 mM) and terbium-labeled anti-pSTAT1 (pTyr701) antibody (final 2 nM) (Invitrogen, catalog no. PV4844) (TR-FRET antibody dilution buffer (Invitrogen, catalog no. PV3574) Prepared to stop the enzyme reaction and generate a TR-FRET signal. After incubation for 30 minutes at room temperature, the plate was read on a Tecan Infinite F200 Pro with the following settings: excitation 340 nm (30) / emission 1 495 nm (10) / emission 2 520 nm (25). The TR-FRET value was a dimensionless number calculated as the ratio of acceptor (green fluorescent protein) signal to donor (terbium) signal. The percent inhibition was calculated as (100%-percentage of compound treatment / DMSO vehicle treatment). To generate a dose response curve, an _{IC 50,} it was calculated by non-linear sigmoidal curve fitting using GraphPad Prism.

The results are summarized in Tables 1 and 2. In Table 1, A represents a value of 500 nM or less, B represents a value greater than 500 nM but less than 1 μM, C represents a value greater than 1 μM but less than 5 μM, and D represents a value greater than 5 μM. In Table 2, A 'represents a ratio greater than 8, B' represents a ratio of 8 or less but not less than 4, C 'represents a ratio of 4 or less but not less than 2, and D' represents a ratio of 2 or less. Represent. Selectivity is expressed as the ratio of the IC ₅₀ value of the compound to the two kinases to be compared. For example, the selectivity of a compound for JAK1 over JAK2 is expressed as the ratio of the IC ₅₀ value for JAK2 to the IC ₅₀ value for JAK1 of the compound, thus the larger the ratio, the more the compound is for JAK1 It is selective.

Example B
Cellular Assay to Determine Inhibition of Janus Kinase The cellular potency of compounds against the inhibition of JAK1 or JAK2 is determined by measuring the cytokine mediated phosphorylation of STAT protein in TF-1 cells.

Human cytokine of IL-6 (R & D Systems, Catalog No. 206-IL-010 / CF) and GM-CSF (R & D Systems, Catalog No. 215-GM-010 / CF) in D-PBS containing 0.1% BSA (Sigma) , Cat. No. A8577) and human EPO (R & D Systems, Cat. No. 287-TC-500) are reconstituted to 500 U / mL in D-PBS containing 0.1% BSA. TF-1 cells (ATCC, CRL-2003), 2 ng / mL recombinant human GM-CSF, 10% FBS (Gibco, catalog no. 10437-028) and 100 U / mL penicillin-streptomycin (Gibco, catalog no. 15140) Culture in RPMI 1640 (ATCC, Catalog No. 30-2001) supplemented with -122). Cells were maintained and propagated between 1 × 10 ⁵ cells /ML～7.5×10 ⁵ cells / mL. Aliquots of cells from early passages were stored for liquid nitrogen storage. Frozen vials of cells were thawed in a 37 ° C. water bath. The cells were spun to remove the freezing medium. Freshly restored frozen cells were adapted for 5 to 7 days of culture and then used for compound testing. Cells used for compound testing were those with less than 20 subcultures or less than 3 months in culture.

To test the compounds, TF-1 cells were harvested by centrifugation at a density of 3-7 × 10 ⁵ cells / mL. After removing the culture medium, the obtained cell pellet was suspended in HBSS buffer (Gibco, catalog number 14025-092) containing 0.1% BSA and washed once by centrifugation. The cell pellet was resuspended at 7.5 × 10 ⁶ cells / mL in HBSS buffer. Four microliters of cells (3 × 10 ⁴ cells total) were added to each well of a white 384-well plate (Packard, Cat. No. 6005214).

  The compound is first diluted in dimethyl sulfoxide (DMSO) (Sigma, Cat. No. D2650) to make nine-step 3-fold diluted dose concentrations in 96 well polypropylene plates (Corning, Cat. No. 3365), and then 125 times more HBSS buffer was added for dilution. To this cell 2 μL of diluted compound was added and the plate mixed by tapping several times. The cells were incubated for 2 hours of treatment. DMSO was used as a control, diluted similarly and added to the cells.

  To assay JAK1 inhibition, 2 μL of IL-6 (diluted to 400 ng / mL (4 ×) in HBSS with 0.1% BSA) was added to the treated cells. Cells were then incubated for 30 minutes of cytokine treatment and at the end, lysed by the addition of 2 μL of 5 × AlphaLISA SureFire Ultra Lysis Buffer (Perkin Elmer). Plates were agitated for 10 minutes at room temperature on a plate shaker. JAK1 activity of cells was determined by measuring STAT3 phosphorylation of Tyr705 in lysates (using AlphaLISA SureFire Ultra kit (Perkin Elmer, Cat. No. ALSU-PST3-A500)). A volume of 5 μL of acceptor mix and donor mix was sequentially added to the lysate according to the product protocol. Assay signals were recorded on an EnVision plate reader (Pekin Elmer) with AlphaScreen optical settings.

  The results are summarized in Table 3. In the table, A represents a value of 500 nM or less, B represents a value of more than 500 nM but less than 1 μM, C represents a value of more than 1 μM but less than 5 μM, and D represents a value of more than 5 μM.

  To assay JAK2 inhibition, 2 μL of EPO diluted to 100 U (4 ×) is added to compound treated cells to stimulate downstream STAT5 phosphorylation of Tyr694 / 699. JAK2 activity of cells is measured by measuring STAT5 phosphorylation (using the AlphaLISA SureFire Ultra kit (Perkin Elmer, Cat. No. ALSU-PST5-A500)).

Example C
Human Whole Blood Assay to Determine Inhibition of Janus Kinase The potency of compounds against the inhibition of JAK1 and JAK2 in human whole blood (HWB) is described by Fridman et al., J. Immunol. 2010, 184, 5298-5307; Clark et al. al., J. Med. Chem. 2014, 57, 5023-5038; and Rompaey et al., J. Immunol. 2013, 191, 3568-3577.

  For example, test compounds are prepared as 30 mM stock solutions in 100% DMSO and then diluted to 5 mM. Ten serial 2.5 dilution series are made in DMSO, the maximum concentration is 5 mM. Further dilution is performed by adding 4 μL of solution in 96 μL of PBS. The maximum concentration is 200 μM. After adding 90 μL of HWB per well to a 96 well polypropylene plate, add 5 μL of the compound solution to a maximum concentration of 10 μM. The plates are mixed and incubated for 45 minutes at 37 ° C. In each well, 5 μl of IFNα at a final concentration of 5,000 U / mL, IL-6 at a final concentration of 100 ng / mL, IL-15 at a final concentration of 100 ng / mL, IL-12 at 100 ng / mL At final concentration, add IL-23 at a final concentration of 100 ng / mL or D-PBS as a control; mix; incubate at 37 ° C. for 15 minutes. The reaction is quenched by adding lysis / fixation buffer to all wells at 1,000 μl / well and samples are incubated for 20 minutes at 37 ° C. After washing the sample with FACS buffer containing 0.1% BSA and 0.1% sodium azide, add 400 μL ice cold 90% methanol / water to each well and incubate on ice for 30 minutes . One more wash with cold FACS buffer and finally all samples at a 1: 125 dilution (in FACS buffer) in 250 μL / well of the desired fluorochrome labeled anti-phospho-STAT antibody (BD) Resuspend. After overnight incubation at 4 ° C., all samples are transferred into 96 well polypropylene U-bottom plates and STAT phosphorylation is analyzed and quantified using a FACS Canto flow cytometer.

  Alternatively, after incubation for 30 minutes at 37 ° C. with the compound, HWB can be recombinant human IL-6 (10 ng / mL), recombinant human IL-2 (4 ng / mL), universal IFN-α (1,000 U) / ML; PBL), recombinant human GM-CSF (20pg / mL) or vehicle (PBS + 0.1% BSA) for 20 min at 37 ° C and treated with prewarmed 1x lysis / fixing buffer Then lyse the RBCs and fix the white blood cells. The cells are permeabilized with 100% methanol, and anti-pSTAT1 and anti-CD4 (IL-6- and IFN-α induced samples), anti-pSTAT5 and anti-CD4 Abs (IL-2 induced sample) or anti-pSTAT5 and anti-CD33 Abs (GM) Were incubated at 4 ° C. for 30 minutes, washed once with PBS, and analyzed on a FACSCanto II flow cytometer.

  Alternatively, in stimulation experiments, various concentrations of test compounds are added for 10 minutes followed by stimulation with human IL-6 (100 ng / mL) at 37 ° C. for 15 minutes. RBC is dissolved using hypotonic conditions. The WBCs are then immediately pelleted and lysed to generate whole cell extracts. This extract is analyzed for phosphorylated STAT3 by using a phospho-STAT3 specific ELISA.

Example D
Collagen-Induced Arthritis Rat Model Collagen-induced arthritis (CIA) is an experimental autoimmune disease that can be induced in liquid susceptible strains of rodents (rat and mouse) by immunization with type II collagen (CII). After immunization, animals develop autoimmune-mediated polyarthritis which shares some clinical, histologic and immunological characteristics with human rheumatoid arthritis. For example, Cremer et al., Curr. Protoc. Immunol. 1996, 15, 1-24; Kawahito et al., J. Immunol. 1998, 161, 4411-4419; Kliwinski et al., J. Autoimmun. 2005, 25. , 165-171.

  A total of 15 female Lewis rats are included in the Bejing Vital River Laboratory Animal Co. Ltd. Obtained from The rats were approximately 5-6 weeks old with no pathogens on arrival. On arrival (day 0), rats were immunized intradermally with a total of 0.5 mL of CII (Sichuan University) / IFA emulsion (Sigma, catalog number F5506) (1 mg of bovine type II collagen). The emulsion was injected at three sites in each rat, one at the base of the tail (0.1 mL) and the remaining two sites (0.2 mL / site) near the base of the back and tail. An identical booster injection was given 7 days after prime immunization.

  For administration, compound 14 was formulated as a suspension using 0.5% sodium carboxymethylcellulose (Sinopharm Chemical Reagent, Catalog No. 30036365). The compound suspension was prepared fresh for each oral administration.

  Thirteen rats were then randomized into two groups using BioBook software to have similar mean disease scores (about 3) and mean weight. Group 1 was a control (vehicle) group of 5 rats. The second group is a treatment group of eight rats. Each rat in group 1 is treated orally (po) with vehicle (10 mL / kg) and each rat in group 2 is orally (p.2) with compound (10 mL / kg, 10 mg / kg). Treated once a day (q. d.) with o.). Disease progression was monitored by measuring the foot volume of the hind paws and scoring the arthritis severity of the four paws.

  The severity of the pathological changes of the four paws of rats was scored prior to primary immunization on day 0, then twice weekly scoring was started from day 7 after sensitization. The criteria for scoring arthritis are: (i) score 0: no signs of erythema and swelling; (ii) score 1: erythema and mild swelling limited to the middle of the foot (foot base) or the ankle joint; (iii 2.) score 2: erythema and mild swelling extending from the ankle to the center of the foot; (iv) score 3: erythema and moderate swelling extending from the ankle to the metatarsal joint; and (v) score 4: ankle, foot and fingers Was surrounded by erythema and severe swelling. The arthritis scores of the rats measured are shown in FIG. In the figure, P <0.05 is regarded as statistically significant.

  Rat hindpaw volume was pre-measured prior to primary immunization on day 0 and then measured twice weekly in Plethysmometer from day 7 to day 27. The change in volume from baseline measurements (day 0) was recorded. The measured increase in rat foot volume is shown in FIG. In the figure, P <0.05 is regarded as statistically significant.

  Rat weights were pre-measured prior to primary immunization and then measured twice weekly from day 7 to day 27. The measured weight of the rat is shown in FIG.

Example E
Pharmacokinetics PK parameters of compound 14 are determined by HPLC-MS / MS (Shimadzu) in Sprague-Dawley rats (Hubei Provincial Laboratory Animal Research Center) after single oral (po) and intravenous (iv) administration. It measured using LC-20ACXR HPLC coupled with AB Sciex API 4500 Qtrap).

  A sensitive and specific HPLC-MS / MS method was developed for the determination of compounds in rat plasma. Multiple Reaction Monitoring (MRM) mode was used for the determination of compounds by monitoring of ion transitions at m / z 443.1 to 375.1. Compound 2 was used as an internal standard and monitored by ion transition at m / z of 427.1 to 357.1. Standard curves ranging from 1.00 to 1000 ng / mL in rat plasma extracts were generated by 1 / × 2 weighted quadratic regression. The regression coefficient obtained was greater than 0.99, and the back calculated value was within ± 15% of the preparation concentration. The results are summarized in Table 4 below.

For intravenous administration, the compound was dissolved in 25% PEG200 containing saline and administered intravenously at a single dose of 1.00 mg / kg. For oral administration, the compound was suspended in 0.5% sodium carboxymethylcellulose (CMC-Na) solution and administered intragastrically at a single dose of 5.00 mg / kg. Approximately 0.200 mL blood samples were collected from the orbital venous plexus at 0 (pre-dose), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose. All samples were placed in EDTA-K ₂ treated tubes and centrifuged at 3,500 rpm for 10 minutes at 4 ° C. to separate plasma fractions. Plasma samples were stored at -20 ° C until analysis. Plasma samples were analyzed by HPLC-MS / MS method.

Example 1
N- (5- (4-((1,1-dioxo-1-thiomorpholino) methyl) phenyl) imidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide 1

  Step 1: tert-Butyl 5-bromoimidazo [1,2-a] pyridin-2-ylcarbamate

In a stirred solution of 5-bromoimidazo [1,2-a] pyridine-2-carboxylic acid (1.00 g, 4.15 mmol, 1.0 eq) in t-BuOH (20 mL) and toluene (20 mL), DPPA (1.37 g, 5.00 mmol, 1.2 eq) was added at ice water bath temperature. Was _then added dropwise Et 3 N (0.70mL, 5.00mmol, 1.2 eq). The resulting mixture was heated to reflux for 14 hours. TLC indicated the disappearance of 5-bromoimidazo [1,2-a] pyridine-2-carboxylic acid. The crude reaction mixture was concentrated to dryness. The residue was purified by column chromatography (200-300 mesh silica gel, PE / EA = 5/1) to give tert-butyl 5-bromoimidazo [1,2-a] pyridin-2-ylcarbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.14 (br, 1 H), 7.82 (s, 1 H), 7.47 (d, J = 8.7 Hz, 1 H), 7.24 (d, J = 6.8 Hz, 1 H), 7.16-7.20 (m, 1 H), 1.49 (s, 9 H).

  Step 2: 5-bromoimidazo [1,2-a] pyridin-2-amine

TFA (10 mL) in a stirred solution of tert-butyl 5-bromoimidazo [1,2-a] pyridin-2-ylcarbamate (0.70 g, 2.24 mmol, 1.0 equiv) in DCM (30 mL) at ice water bath temperature It dripped at. The resulting mixture was stirred at ambient temperature for 6 hours. TLC indicated the disappearance of tert-butyl 5-bromoimidazo [1,2-a] pyridin-2-ylcarbamate. The reaction mixture was concentrated to dryness then treated with water and DCM. The aqueous phase was extracted twice with DCM. The aqueous phase was then treated with 6N aqueous NaOH solution to pH> 9 and extracted twice with DCM. The combined organic phases were dried over Na ₂ SO ₄ and concentrated to dryness to give 5-bromoimidazo [1,2-a] pyridin-2-amine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 7.24 (d, J = 8.4 Hz, 1 H), 7.05 (dd, J = 1.1, 6.8 Hz, 1 H ), 6.97-7.01 (m, 2H), 5.31 (br, 2H).

  Step 3: N- (5-bromoimidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide

A solution of 5-bromoimidazo [1,2-a] pyridin-2-amine (0.28 g, 1.32 mmol, 1.0 eq) in ACN (20 mL) in a stirred solution of cyclopropanecarboxylic acid chloride (0.48 g, After dropwise addition of 62 mmol, 3.5 equivalents) Et ₃ N (0.65 mL, 4.62 mmol, 3.5 equivalents) was added dropwise at ice water bath temperature. The resulting mixture was stirred at ambient temperature for 24 hours. TLC indicated the disappearance of 5-bromoimidazo [1,2-a] pyridin-2-amine. Saturated NH ₃ / EtOH (30 mL) was added and the resulting mixture was stirred at ambient temperature for 6 hours. The crude reaction mixture was concentrated to dryness and the residue was treated with water. The precipitate was collected, dried and then washed with EA to give N- (5-bromoimidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.14 (br, 1 H), 8.05 (s, 1 H), 7.50-7.52 (m, 1 H), 7.19 -7.28 (m, 2H), 1.92-1.99 (m, 1 H), 0.82-0.84 (m, 4H).

  Step 4: 4- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) -1,1-dioxo-1-thiomorpholine

2- (4- (bromomethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.00 g, 16.8 mmol, 0.6 eq) in MeOH (50 mL) and DCM To a stirred solution contained in (150 mL) was added dropwise DIPEA (11.30 g, 87.3 mmol, 3.0 eq) at ice water bath temperature, then 1,1-dioxo-1-thiomorpholine HCl salt (5.00 g, 29.1 mmol, 1.0 eq.) Were added in portions. The resulting mixture was stirred at ambient temperature for 16 hours. TLC showed the disappearance of 2- (4- (bromomethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The crude reaction mixture was concentrated to dryness and the resulting residue was treated with water. The precipitate is collected, dried and 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) -1,1-dioxo-1-thio Obtained morpholine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 7.56 (d, J = 7.8 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 2 H), 3. 69 (s, 2 H), 3.09-3.11 (m, 4 H), 2.85-2. 86 (m, 4 H), 1. 29 (s, 12 H).

Step 5: N- (5- (4-((1,1-dioxo-1-thiomorpholino) methyl) phenyl) imidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide N- (5- Bromoimidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide (0.17 g, 0.61 mmol, 1.0 equivalent) and 2- (4- (bromomethyl) phenyl) -4,4,5, To a stirred solution of 5-tetramethyl-1,3,2-dioxaborolane (0.26 g, 0.73 mmol, 1.2 eq) in dioxane (30 mL) K ₂ CO ₃ (0.17 g, 1.22 mmol, After adding a solution of 2.0 eq) in water (10 mL), a catalytic amount of Pd (dppf) Cl ₂ was added. The resulting mixture was heated to reflux under a nitrogen atmosphere for 12 hours. The reaction mixture is concentrated to dryness and the residue obtained is purified by column chromatography (200-300 mesh silica gel, DCM / MeOH = 20/1) and then further purified using PE / EA, N- (5 There was obtained-(4-((1,1-dioxo-1-thiomorpholino) methyl) phenyl) imidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.02 (br, 1 H), 7.91 (s, 1 H), 7.67-7.68 (m, 2 H), 7.56 -7.58 (m, 2 H), 7.45-7.47 (m, 1 H), 7.31-7. 35 (m, 1 H), 6.86-6.88 (m, 1 H), 3 .79 (s, 2H), 3.15 (m, 4H), 2.95 (m, 4 H), 1.92 (m, 1 H), 0.76-0.78 (m, 4 H); LC -MS (m / z): 425 [M + H] ^< +>.

Compounds 2-12 in Tables 5-1, 5-2, 5-3 were prepared according to the procedure described in Example 1. NMR spectral data are reported in δ ppm using a 400 MHz spectrometer and DMSO-d ₆ as solvent.

Example 2
N- (5- (4- (1,1-dioxo-1-thiomorpholine-4-carbonyl) phenyl) imidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide 13

  Step 1: (4-Bromophenyl) (1,1-dioxo-1-thiomorpholino) methanone

4-Bromobenzoyl chloride (200 mg, 0.91 mmol, 1.0 equivalents) in a stirred suspension of 1,1-dioxo-1-thiomorpholine HCl salt (188 mg, 1.1 mmol, 1.2 equivalents) in DCM (50 mL) ) Was added followed by Et ₃ N (276 mg, 2.73 mmol, 3.0 eq). The resulting mixture was stirred at ambient temperature for 16 hours. TLC indicated the disappearance of 4-bromobenzoyl chloride. The reaction mixture was concentrated to dryness and then treated with water. The resulting precipitate was collected by filtration and dried to give (4-bromophenyl) (1,1-dioxo-1-thiomorpholino) methanone. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 7.67 (d, J = 6.3 Hz, 2 H), 7.46 (d, J = 6.2 Hz, 2 H), 3. 68-3.98 (m, 4H), 3.25 (m, 4H).

Step 2: N- (5- (4- (1,1-dioxo-1-thiomorpholine-4-carbonyl) phenyl) imidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide (4-bromo Phenyl) (1,1-dioxo-1-thiomorpholino) -methanone (50 mg, 0.16 mmol, 1.2 equivalents) and B ₂ (pin) ₂ (41 mg, 0.16 mmol, 1.2 equivalents), 1, 1,4-dioxane _K solid to a stirred solution containing in _{(10mL) 2 CO 3 (36mg} , 0.26mmol, 2.0 eq) was added, was added a catalytic amount of Pd (dppf) Cl _2. The resulting mixture was heated to reflux under a nitrogen atmosphere for 16 hours. TLC showed the disappearance of (4-bromophenyl) (1,1-dioxo-1-thiomorpholino) methanone. After cooling the reaction mixture to ambient temperature, add N- (5-bromoimidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide (36 mg, 0.13 mmol, 1.0 eq) followed by Te _{K 2 CO 3 (36mg, 0.26mmol} , 2.0 eq) was added water (3 ml) solution of. The resulting mixture was heated to reflux under a nitrogen atmosphere for 4 hours. TLC indicated the disappearance of N- (5-bromoimidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide. The reaction mixture is concentrated to dryness, and the resulting residue is purified by column chromatography (200-300 mesh silica gel, DCM / MeOH = 40/1) to give N- (5- (4- (1,1-dioxo- 1-thiomorpholine-4-carbonyl) phenyl) imidazo [1,2-a] pyridin-2-yl) cyclopropanecarboxamide was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.04 (s, 1 H), 7.93 (s, 1 H), 7.80 (m, 2 H), 7.73 (m, 2 H) ), 7.49-7.51 (m, 1 H), 7. 35 (m, 1 H), 6.92-6. 93 (m, 1 H), 3.86-4. 04 (m, 8 H), 1. 92 (m, 1 H), 0.77 (m, 4 H); LC-MS (m / z): 439 [M + H] ^< +>.

  Compounds 14, 16 and 17 of Table 6 were prepared according to the procedure described in Example 2.

Example 3
5- (2-Fluoro-4- (1,1-dioxo-1-thiomorpholinomethyl) phenyl) imidazo [1,2-a] pyridin-2-amine 18

  Step 1: 4- (4-bromo-3-fluorobenzyl) -1,1-dioxo-1-thiomorpholine

To a stirred solution of 1,1-dioxo-1-thiomorpholine HCl salt (100 mg, 0.58 mmol, 1.0 eq) in DCM (30 mL) and MeOH (10 mL) was added DIPEA (225 mg, 1.74 mmol, 3. 0 equivalents) was added. The resulting mixture was stirred at ambient temperature for 10 minutes. 1-Bromo-4- (bromomethyl) -2-fluorobenzene (94 mg, 0.35 mmol, 0.6 eq.) In DCM (3 mL) was added. The resulting mixture was heated to reflux for 8 hours. TLC indicated the disappearance of 1-bromo-4- (bromomethyl) -2-fluorobenzene. The crude reaction mixture was concentrated to dryness and the resulting residue was treated with water. The mixture is extracted with EA, dried over Na ₂ SO ₄ , concentrated to dryness, 4- (4-bromo-3-fluorobenzyl) -1,1-dioxo-1-thiomorpholine (88 mg, 78% yield) Rate), which was used directly in the next step without further purification.

Step 2: 5- (2-Fluoro-4- (1,1-dioxo-1-thiomorpholinomethyl) phenyl) imidazo [1,2-a] pyridin-2-amine 4- (4-bromo-3-fluoro) Benzyl) -1,1-dioxo-1-thiomorpholine (42 mg, 0.13 mmol, 1 equivalent) and B ₂ (pin) ₂ (41 mg, 0.16 mmol, 1.2 equivalents) in 1,4-dioxane (10 mL) Solid K ₂ CO ₃ (36 mg, 0.26 mmol, 2.0 eq) was added to the stirred solution contained in) followed by catalytic amount of Pd (dppf) Cl ₂ . The resulting mixture was heated to reflux under a nitrogen atmosphere for 16 hours. TLC showed the disappearance of 4- (4-bromo-3-fluorobenzyl) -1,1-dioxo-1-thiomorpholine. After cooling the reaction mixture to ambient temperature, tert-butyl 5-bromoimidazo [1,2-a] pyridin-2-ylcarbamate (41 mg, 0.13 mmol, 1.0 eq) is added, followed by K ₂ A solution of CO ₃ (36 mg, 0.26 mmol, 2.0 eq) in water (3 mL) was added. The resulting mixture was heated to reflux under a nitrogen atmosphere for 4 hours. TLC indicated the disappearance of tert-butyl 5-bromoimidazo [1,2-a] pyridin-2-ylcarbamate. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM and washed with brine. The aqueous layer was extracted with DCM. The combined organic layers are dried (Na ₂ SO ₄ ), concentrated and tert-butyl 5- (2-fluoro-4- (1,1-dioxo-1-thiomorpholinomethyl) phenyl) imidazo [1,2-] a] Pyridin-2-ylcarbamate was obtained as a yellow residue. The residue was dissolved in 1 mL of DCM and 0.3 mL of TFA was added at ice water temperature. The solution was stirred at ambient temperature for 6 hours. The solution was diluted with DCM and washed with 1 N NaOH. The aqueous layer was extracted with DCM. The combined organic layers are dried (Na ₂ SO ₄ ), concentrated and purified by column chromatography (200-300 mesh silica gel, DCM / MeOH = 30/1) to give 5- (2-fluoro-4- (1) 1,1-dioxo-1-thiomorpholinomethyl) -phenyl) imidazo [1,2-a] pyridin-2-amine (6 mg, 13%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 7.34-7.61 (m, 6 H), 6.94 (s, 1 H), 6.12 (bs, 2 H), 3.82 (S, 2H), 3.17 (m, 4H), 2.96 (m, 4H), 1.98 (m, 1H), 0.75 (m, 4H); LC-MS (m / z) : 343 [M + H] ^< +>.

  Compounds 20-35 of Tables 7-1, 7-2, 7-3, and 7-4 were prepared according to the procedures described in Examples 1-3.

  The examples given above are provided to the person skilled in the art to give a complete disclosure and description of how to make and use the claimed embodiments and the description. It is not intended to limit the scope of what has been disclosed. Variations apparent to those skilled in the art are intended to be included within the scope of the following claims. All publications, patents and patent applications mentioned in this specification are, by reference, as if each such publication, patent and patent application was specifically incorporated herein by reference. As incorporated herein.

Claims (20)

Formula ( D ):
(In the formula:
L ¹ is —C (O) R ² , where
R ² _is, C 1 -C ₈ alkyl luma other is an _C 3 _{-C 10} cycloalkyl;
L ² is a single bond or -C (O)-;
R ³ represents cyano, cyanomethylphenylamino, 3,3,3-trifluoropropanamide, hydroxypyrrolidinyl, piperidinyl, cyanopiperidinyl, morpholino, 1,1-dioxide thiomorpholino, methoxy, dimethylazetidiny Le or cyclopropane sulfonamide;
R ⁴ is independently hydrogen or C ₁ -C ₈ alkyl,
R ⁵ is halogen or C ₁ -C ₈ alkyl,
R ^L is hydrogen;
m is an integer of 0 or 1;
n is an integer of 0 ;
i is an integer of 0 or 1 )
Or a stereoisomer, enantiomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. R ² _is C 1 -C ₈ alkyl, A compound according to claim 1. The compound of claim 1 wherein R ² is isopropyl. The compound according to claim 1, wherein R ² is C ₃ -C ₁₀ cycloalkyl. R ² is cyclopropyl or cyclobutyl, A compound according to claim 4. R ² is cyclopropyl A compound according to claim 4. A compound according to claim 1 which is selected from, or isotopic variant; or a pharmaceutically acceptable salt or solvate thereof. It is a mixture of enantiomers of a compound according to any one of claims 1 to 7 mixture of enantiomers. A mixture of diastereomers, which is a mixture of diastereomers of the compound according to any one of claims 1 to 7 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 , an enantiomer mixture according to claim 8 or a diastereomer mixture according to claim 9 , and a pharmaceutically acceptable excipient. . 11. The pharmaceutical composition of claim 10 , formulated for single dose administration. 12. The pharmaceutical composition according to claim 10 or 11 formulated as an oral dosage form, a parenteral dosage form or an intravenous dosage form. The pharmaceutical composition according to claim 12 , wherein the oral dosage form is a tablet or a capsule. The pharmaceutical composition according to any one of claims 10 to 13 , further comprising a second therapeutic agent. Use for the preparation of a medicament for treating, preventing or ameliorating one or more symptoms of a Janus kinase mediated disorder, disease or condition in a subject, comprising
Said disorder, disease or condition is proliferative disease, inflammatory disease, immune disease, rheumatoid arthritis, asthma, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, alopecia, dry eye, allergy, amyotrophic lateral sclerosis , Ankylosing spondylitis, arthritis, atopic dermatitis, Behcet's disease, celiac disease, colitis, chronic obstructive pulmonary disease, leukemia, lymphoma, myelofibrosis, multiple sclerosis, osteoarthritis, polycythemia, Primary biliary cirrhosis, rhinitis, dryness syndrome, Sjogren's syndrome, solid tumor, systemic lupus erythematosus, transplant rejection, ulcerative colitis or vitiligo, myeloproliferative disorder, pancreatic cancer or erythrocytosis 11. Use of a compound according to any one of 1 to 7 , use of an enantiomer mixture according to claim 8 , use of a diastereomer mixture according to claim 9 , or claim 10 Use of a pharmaceutical composition according to any one of 1-14. Use for the preparation of a medicament for treating, preventing or ameliorating one or more symptoms of a JAK1-mediated disorder, disease or condition in a subject, comprising
Said disorder, disease or condition is proliferative disease, inflammatory disease, immune disease, rheumatoid arthritis, asthma, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, alopecia, dry eye, allergy, amyotrophic lateral sclerosis , Ankylosing spondylitis, arthritis, atopic dermatitis, Behcet's disease, celiac disease, colitis, chronic obstructive pulmonary disease, leukemia, lymphoma, myelofibrosis, multiple sclerosis, osteoarthritis, polycythemia, Primary biliary cirrhosis, rhinitis, dryness syndrome, Sjogren's syndrome, solid tumor, systemic lupus erythematosus, transplant rejection, ulcerative colitis or vitiligo, myeloproliferative disorder, pancreatic cancer or erythrocytosis 11. Use of a compound according to any one of 1 to 7 , use of an enantiomer mixture according to claim 8 , use of a diastereomer mixture according to claim 9 , or claim 10 Use of a pharmaceutical composition according to any one of 1-14. Use for the preparation of a medicament for treating, preventing or ameliorating one or more symptoms of a JAK2-mediated disorder, disease or condition in a subject, comprising
Said disorder, disease or condition is proliferative disease, inflammatory disease, immune disease, rheumatoid arthritis, asthma, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, alopecia, dry eye, allergy, amyotrophic lateral sclerosis , Ankylosing spondylitis, arthritis, atopic dermatitis, Behcet's disease, celiac disease, colitis, chronic obstructive pulmonary disease, leukemia, lymphoma, myelofibrosis, multiple sclerosis, osteoarthritis, polycythemia, Primary biliary cirrhosis, rhinitis, dryness syndrome, Sjogren's syndrome, solid tumor, systemic lupus erythematosus, transplant rejection, ulcerative colitis or vitiligo, myeloproliferative disorder, pancreatic cancer or erythrocytosis 11. Use of a compound according to any one of 1 to 7 , use of an enantiomer mixture according to claim 8 , use of a diastereomer mixture according to claim 9 , or claim 10 Use of a pharmaceutical composition according to any one of 1-14. Use for the preparation of a medicament for treating, preventing or ameliorating one or more symptoms of a JAK 3-mediated disorder, disease or condition in a subject, comprising
Said disorder, disease or condition is proliferative disease, inflammatory disease, immune disease, rheumatoid arthritis, asthma, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, alopecia, dry eye, allergy, amyotrophic lateral sclerosis , Ankylosing spondylitis, arthritis, atopic dermatitis, Behcet's disease, celiac disease, colitis, chronic obstructive pulmonary disease, leukemia, lymphoma, myelofibrosis, multiple sclerosis, osteoarthritis, polycythemia, Primary biliary cirrhosis, rhinitis, dryness syndrome, Sjogren's syndrome, solid tumor, systemic lupus erythematosus, transplant rejection, ulcerative colitis or vitiligo, myeloproliferative disorder, pancreatic cancer or erythrocytosis 11. Use of a compound according to any one of 1 to 7 , use of an enantiomer mixture according to claim 8 , use of a diastereomer mixture according to claim 9 , or claim 10 Use of a pharmaceutical composition according to any one of 1-14. Use for the preparation of a medicament for treating, preventing or ameliorating one or more symptoms of a TYK2-mediated disorder, disease or condition in a subject, comprising
Said disorder, disease or condition is proliferative disease, inflammatory disease, immune disease, rheumatoid arthritis, asthma, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, alopecia, dry eye, allergy, amyotrophic lateral sclerosis , Ankylosing spondylitis, arthritis, atopic dermatitis, Behcet's disease, celiac disease, colitis, chronic obstructive pulmonary disease, leukemia, lymphoma, myelofibrosis, multiple sclerosis, osteoarthritis, polycythemia, Primary biliary cirrhosis, rhinitis, dryness syndrome, Sjogren's syndrome, solid tumor, systemic lupus erythematosus, transplant rejection, ulcerative colitis or vitiligo, myeloproliferative disorder, pancreatic cancer or erythrocytosis 11. Use of a compound according to any one of 1 to 7 , use of an enantiomer mixture according to claim 8 , use of a diastereomer mixture according to claim 9 , or claim 10 Use of a pharmaceutical composition according to any one of 1-14. Wherein the subject is a human The use according to any one of claims 15-19.